tag:blogger.com,1999:blog-65219851764167919262024-03-18T08:00:31.906-07:00PharmGKB BlogMark Woonhttp://www.blogger.com/profile/11238496801487705858noreply@blogger.comBlogger470125tag:blogger.com,1999:blog-6521985176416791926.post-79903893162136814742024-03-18T08:00:00.000-07:002024-03-18T08:00:00.151-07:00PharmCAT Tutorial Videos Now Available on YouTubePharmacogenomics Clinical Annotation Tool (PharmCAT) tutorial videos are now available on the <a href="https://www.youtube.com/channel/UCnYHYK_5HD1Lt2N_B4FsTYQ" target="_blank">PharmGKB YouTube channel</a>. The tutorial videos provide clear, step-by-step instructions for running PharmCAT from command lines. By providing genotype-based drug prescribing recommendations, we hope to engage the wider genomics community and create a standard for the use in precision medicine. <br /><br />The first two videos cover (1) the <a href="https://youtu.be/PjVdtMp8oRI?si=mRaiaU6EVEEd6dJL" target="_blank">introduction to PharmCAT, modules, and reports</a> and (2) a hands-on example that walks you through the setup and commands for <a href="https://youtu.be/d1IZPLOrPOE?si=LREY8RI-wz-5PoqN" target="_blank">running PharmCAT</a>.<div><br />Future videos will cover how to supply external pharmacogenomic calls to PharmCAT, how to use ‘Research’ modes, how to use the PharmCAT functionalities for biobank-scale analyses, and more.</div><div> <br />More information about PharmCAT can be found at <a href="https://pharmcat.org/" target="_blank">https://pharmcat.org/</a>. To follow PharmCAT, subscribe to the <a href="https://www.youtube.com/channel/UCnYHYK_5HD1Lt2N_B4FsTYQ" target="_blank">PharmGKB YouTube channel</a> for new videos or the <a href="https://pharmgkb.us10.list-manage.com/subscribe?u=c46dea014a68524407fdbffa1&id=d0d1ec73ab" target="_blank">PharmCAT mailing list</a> for the latest PharmCAT updates.</div><div><br />If you have questions regarding PharmCAT, please contact us at pharmcat@pharmgkb.org.<p><span id="docs-internal-guid-607d0fd2-7fff-14a8-5b0e-6ff93b11a654"></span></p></div>Binglan Lihttp://www.blogger.com/profile/08207707001424607298noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-25898987254068924292024-03-14T10:05:00.000-07:002024-03-14T10:05:49.481-07:00NAT2 now released on PharmVar<p class="MsoNormal" style="background: white; line-height: normal; margin: 12pt 0in 0in;"><span style="font-family: arial;"><span lang="EN-GB">PharmVar and PharmGKB are excited to share that <i>NAT2 </i>has been transitioned into the PharmVar database and updated accordingly on <a href="https://www.pharmgkb.org/gene/PA18/haplotype" target="_blank">PharmGKB</a></span><span lang="EN-GB">. NAT2 metabolizes several pharmaceutical substrates, including isoniazid, hydralazine, amifampridine, procainamide and sulfonamides, as well as some highly carcinogenic arylamines. NAT2 enzymatic activity varies considerably between individuals, due to polymorphisms in <i>NAT2 </i>coding sequence that may be found more commonly in some populations than others. <i>NAT2 </i>alleles usually contain more than one single nucleotide variation (SNV), with specific </span>variants defining different allelic groups. Given the complex haplotypic nature of <i>NAT2 </i>alleles, phasing of SNVs to determine diplotype from genotype can be difficult. <span lang="EN-GB">It is therefore important to maintain up-to-date information regarding sequence variation and star allele (haplotype) definitions to facilitate accurate genetic testing, genotype interpretation and phenotype prediction in the research and clinical settings.</span><span lang="EN-GB"><o:p></o:p></span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin: 12pt 0in 0in;"><span style="font-family: arial;"><span lang="EN-GB">Some drastic changes have been made to <i>NAT2 </i>nomenclature during transition from the original</span><span lang="EN-GB" style="color: #444444;"> </span><span lang="EN-GB"><span style="color: purple;"><a href="http://nat.mbg.duth.gr/" target="_blank">Database of Arylamine <i>N</i>-Acetyltransferases (NATs)</a></span></span><span lang="EN-GB"> to the new </span><span lang="EN-GB">“star” allele definitions on <a href="https://www.pharmvar.org/gene/NAT2" target="_blank">PharmVar</a>:</span><span lang="EN-GB"><o:p></o:p></span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin: 12pt 0in 0in;"><span style="font-family: arial;"><b><span lang="EN-GB">The <i>NAT2 </i>reference allele has now changed:</span></b><span lang="EN-GB"> T</span><span lang="EN-GB">he NG_012246.1 RefSeq differs from X14672.1 (which was used in the past to define star alleles) at the position that corresponds to c.803 (rs1208), where X14672.1 has “A” while NG_012246.1 has “G”. Thus, depending on which reference sequence is utilized, this position is reported as either reference or variant. The transition of allele definitions to the NG_012246.1 RefSeq caused “variant switching”, meaning that all star alleles which were previously described as having c.803A>G lost this variant, as “G” is now considered reference, while all other star alleles gained c.803G>A, as “A” is now considered variant. </span><span lang="EN-GB"><o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><span lang="EN-GB" style="color: windowtext;">The new reference allele is now catalogued as <i>NAT2*1</i>:</span></b><span lang="EN-GB" style="color: windowtext;"> The sequence of NG_012246.1 RefSeq corresponds to the allele that was formerly described as <i>NAT2*12A</i>. Its renaming as <i>NAT2*1.001 </i>facilitates the application of PharmVar rules to <i>NAT2 </i>allelic nomenclature, while it also enables the use of <i>NAT2*1</i> name<i> </i>to describe the reference allele, in line with the star allele nomenclature of other pharmacogenes. To avoid confusion during the transition from the legacy to the new nomenclature, <i>*12 </i>is now retired. Having a <i>NAT2*1 </i>allele grouping in place also facilitates NGS analyses using GRCh38 as a reference.<o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><i><span lang="EN-GB" style="color: windowtext;">NAT2*4 </span></i></b><b><span lang="EN-GB" style="color: windowtext;">is no longer considered as the reference allele: </span></b><span lang="EN-GB" style="color: windowtext;">Alleles carrying c.803G>A as their only amino acid changing SNV will be called as <i>*4 </i>according to the new nomenclature. This includes the former <i>NAT2*4 </i>reference allele of sequence X14672.1, now considered a variant and listed as <i>NAT2*4.001</i>. Although this will no longer be used as a reference, it is considered to be functionally equivalent to <i>NAT2*1.001 </i>(formerly <i>NAT2*12A</i>) and may still be used to compare the enzymatic or structural properties of polymorphic NAT2 proteins. <o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><span lang="EN-GB" style="color: windowtext;">Star alleles have been renamed: </span></b><span lang="EN-GB" style="color: windowtext;">Several <i>NAT2 </i>star alleles have been renamed to conform to PharmVar rules during the transition from the legacy nomenclature to the PharmVar database.</span><span lang="EN-GB" style="color: windowtext;"><o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><span lang="EN-GB" style="color: windowtext;">Not </span></b><b><span lang="EN-GB" style="color: windowtext;">all previously defined star alleles have been transferred:</span></b><span lang="EN-GB" style="color: windowtext;"> In the past, it has not always been clear how a <i>NAT2 </i>haplotype was determined. Many have been inferred via computational phase analysis and were not verified experimentally. In the case of haplotypes where the available evidence from the literature was deemed insufficient to support confident allele definition, those haplotypes were not transferred to PharmVar, but they will remain posted on the original</span><span lang="EN-GB"> </span><span lang="EN-GB"><span style="color: purple;"><a href="http://nat.mbg.duth.gr/" target="_blank">Database of Arylamine <i>N</i>-Acetyltransferases (NATs)</a></span></span><span lang="EN-GB" style="color: windowtext;">.<o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><span lang="EN-GB" style="background: white; color: #222222;">PharmGKB-annotated <i>NAT2</i> alleles that are not transitioned into PharmVar will remain on PharmGKB with the original </span><span lang="EN-GB">Database of Arylamine <i>N</i>-Acetyltransferases (NATs)</span><span lang="EN-GB" style="background: white; color: #222222;"> name (e.g., <a href="https://www.pharmgkb.org/haplotype/PA165949124" style="font-style: italic;" target="_blank">NAT2*6J</a>)</span><span lang="EN-GB" style="background: white; color: #222222;">. PharmVar-transitioned <i>NAT2</i> alleles are indicated on PharmGKB <i>NAT2</i> allele pages with the new "PharmVar Allele" tag (e.g., <a href="https://www.pharmgkb.org/haplotype/PA165949098" style="font-style: italic;" target="_blank">NAT2*4</a>)</span><span lang="EN-GB" style="background: white; color: #222222;">.</span><span lang="EN-GB"><o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><span lang="EN-GB" style="color: windowtext;">The requirements for new allele definition have changed: </span></b><span lang="EN-GB" style="color: windowtext;">In the past, reporting only the SNVs in the <i>NAT2 </i>coding region was sufficient to define new star alleles. According to PharmVar rules, new <i>NAT2 </i>alleles<i> </i>must cover SNVs within defined coordinates that enclose the 5’ untranslated region (including the untranslated first exon), the coding exon, the exon/intron junctions, and the entire 3’ untranslated region relative to genomic reference sequence NG_012246.1. Former alleles covering only the coding region have been annotated with a limited evidence level, as they may have additional variants that were not captured when the allele was first defined.<o:p></o:p></span></span></p><p class="Default" style="margin: 0in;"><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"> </span></span></p><p class="Default" style="margin: 0in;"><span style="font-family: arial;"><b><span lang="EN-GB" style="color: windowtext;">During the course of updating <i>NAT2 </i>nomenclature, we have been able to confirm several of the former haplotypes, while also identifying new ones.<i> </i></span></b><b><span lang="EN-GB" style="color: windowtext;">PharmVar encourages submissions of novel haplotypes for star allele definition, as well as for existing definitions to either raise their evidence levels from Limited or Moderate to Definitive, or to solidify their status of Definitive. </span></b><i><span lang="EN-GB" style="color: windowtext;"><o:p></o:p></span></i></span></p><p class="Default" style="margin: 0in;"><b><span lang="EN-GB" style="color: windowtext;"><span style="font-family: arial;"><br /></span></span></b></p><p class="MsoNormal" style="background: white; line-height: normal; margin: 0in 0in 10pt;"><span style="font-family: arial;"><span lang="EN-GB">Additional information has been summarized in the Read Me and Change Log documents available on the </span><span lang="EN-GB"><span style="color: purple;"><a href="https://www.pharmvar.org/gene/NAT2" target="_blank">PharmVar <i>NAT2</i> page</a></span></span><span lang="EN-GB">. Also please consult the “NAT2 Look-up” table available under “More Documents” on the same page for an up-to-date record of alleles transferred and a quick reference of PharmVar and legacy star allele names.<b> </b></span><b><span lang="EN-GB"><o:p></o:p></span></b></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin: 0in;"><span style="font-family: arial;"><span lang="EN-GB">We would like to thank all members of the</span><span lang="EN-GB"> </span><span lang="EN-GB"><a href="https://www.pharmvar.org/expert-panels" target="_blank">PharmVar <i>NAT2</i> Gene Expert Panel</a></span><span lang="EN-GB"> </span><span lang="EN-GB">for their massive contribution to this project, as well as the </span><span lang="EN-GB"><a href="http://nat.mbg.duth.gr/" target="_blank"><i>NAT</i> Gene Nomenclature Committee</a></span><span lang="EN-GB" style="color: #444444;"> </span><span lang="EN-GB">for their services to the NAT community since 1998.</span></span><span lang="EN-GB" style="color: #444444; font-family: Arial, sans-serif; font-size: 11pt;"><o:p></o:p></span></p>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-9620921064156742702024-02-29T10:10:00.000-08:002024-02-29T10:11:47.044-08:00ClinPGx 2024 Registration and Abstract Submission Open<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgijUHaoSu2fJIpA7DeSiRaV0cjeEfMLAPFbvoIvyOQJpnrUtsIfIkIZWi2b0uZ33c9WqgcKqsgJLZuAqzz0mVNjdyBEW4AnH2yR_35I3GLNRcuLWaSvSnB1AkebiqMkWlroPN_D32rr9HO5n2UjJBT6WjocbzQHhyphenhyphenXw_YkixDra0zIek3axyDeOxXESqAg/s544/ClinPGx-Logo@2x.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="376" data-original-width="544" height="148" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgijUHaoSu2fJIpA7DeSiRaV0cjeEfMLAPFbvoIvyOQJpnrUtsIfIkIZWi2b0uZ33c9WqgcKqsgJLZuAqzz0mVNjdyBEW4AnH2yR_35I3GLNRcuLWaSvSnB1AkebiqMkWlroPN_D32rr9HO5n2UjJBT6WjocbzQHhyphenhyphenXw_YkixDra0zIek3axyDeOxXESqAg/w215-h148/ClinPGx-Logo@2x.png" width="215" /></a></div><p style="clear: both; text-align: left;"><span style="font-family: arial; font-size: medium;"><b><i>REGISTRATION OPEN</i></b></span></p><p style="clear: both; text-align: left;"><span face=""Segoe UI", sans-serif" style="background-color: white; caret-color: rgb(0, 0, 0); font-size: 16px;">In collaboration with CPIC, PharmGKB, PharmCAT and PharmVar, the Penn Institute for Biomedical Informatics will be hosting the </span><b style="caret-color: rgb(0, 0, 0); font-family: "Segoe UI", sans-serif; font-size: 16px;">ClinPGx 2024: Knowledge, Implementation, Education</b><span face=""Segoe UI", sans-serif" style="background-color: white; caret-color: rgb(0, 0, 0); font-size: 16px;"> meeting on June 20th and 21st, 2024 in Philadelphia, PA. This meeting will provide educational content to cover all aspects of PGx implementation, including knowledgebases, implementation strategy, informatics, use of AI in precision medicine, clinical laboratory insights, and more.</span></p><div class="separator" style="clear: both; text-align: left;"><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">Participants are invited to submit abstracts for the poster sessions. You must be registered for the meeting before your abstract will be accepted.<o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">Please note breakfast & lunch will be provided all conference days.<o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;"><br /></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;"><a contenteditable="false" href="https://www.eventbrite.com/e/clinpgx-2024-knowledge-implementation-education-tickets-803032270137" target="_blank" title="https://www.eventbrite.com/e/clinpgx-2024-knowledge-implementation-education-tickets-803032270137"><span style="color: blue;">Registration</span></a> and <a href="https://cpicpgx.org/wp-content/uploads/2024/02/ClinPGx-2024-Meeting-Agenda-2.pdf" target="_blank">detailed agenda</a></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;"><br /></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><b><i><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">REMINDERS / DEADLINES:</span></i></b><span face=""Segoe UI", sans-serif" style="font-size: 12pt;"><o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">March 22, 2024: Deadline for Abstract Submission. Abstract submission form link <a contenteditable="false" href="https://redcap.med.upenn.edu/surveys/?s=NEEL9FPEDNL3EN3R" target="_blank" title="https://redcap.med.upenn.edu/surveys/?s=NEEL9FPEDNL3EN3R"><span style="color: blue;">here</span></a>.<o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">April 30, 2024: Deadline for $350 Registration Fee <i>(Starting May 1st, registration fee will be $450)</i><o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">May 20, 2024: Deadline for Hotel Reservations. Click <a contenteditable="false" href="https://upenn.box.com/s/bodll2c8v21rbnbyk00nmpd08dt0rxe0" target="_blank" title="https://upenn.box.com/s/bodll2c8v21rbnbyk00nmpd08dt0rxe0"><span style="color: blue;">HERE </span></a>for hotels offering special rates.<o:p></o:p></span></p><p class="MsoNormal" style="background: white; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; margin: 0in;"><span face=""Segoe UI", sans-serif" style="font-size: 12pt;">June 1, 2024: Deadline to register for the event.</span></p></div><div class="separator" style="clear: both; text-align: left;"><br /></div><br /><br /><p></p>Li Gonghttp://www.blogger.com/profile/07379068611119375369noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-48680219644448338972024-01-25T15:05:00.000-08:002024-02-22T13:40:56.026-08:00Release of Additional PharmGKB Pediatric Drug Summaries<p>A new round of PharmGKB's pediatric drug summaries is now available on PharmGKB under the Pediatric Focus. </p><p>To view the site with the focus active, please select the "Focus" button in the upper right-hand corner and toggle the "Pediatric Focus" setting.</p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjlu7SIRCyeZbpkxny0zPrUfwfLO5ipr4Xjhii8HU-wtns0DDS5awF7ig6qAM52vYuj9kLMhz5cLKhJjmjixZ_fP20-W9mXXFklOyccfvI2xoz9VE3BYCQ65qJWqJi42yTHY4i6RYaZThvpkn8Rf1likyzW7LQ_TeHJkq8SYSYJ25oLZsFCzLDa8O9ymd5f/s1126/screenshot.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="223" data-original-width="1126" height="79" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjlu7SIRCyeZbpkxny0zPrUfwfLO5ipr4Xjhii8HU-wtns0DDS5awF7ig6qAM52vYuj9kLMhz5cLKhJjmjixZ_fP20-W9mXXFklOyccfvI2xoz9VE3BYCQ65qJWqJi42yTHY4i6RYaZThvpkn8Rf1likyzW7LQ_TeHJkq8SYSYJ25oLZsFCzLDa8O9ymd5f/w400-h79/screenshot.png" width="400" /></a></div><p>Users can also access the Pediatric Focus on the<a href="https://www.pharmgkb.org/page/focusIntro" target="_blank"> Focus landing page</a>, or by typing <a href="http://pediatric.pharmgkb.org">pediatric.pharmgkb.org</a>. <br /></p><div>These pediatric drug summaries contain key information relevant to
prenatal, postnatal, and pediatric populations, manually curated from
PharmGKB annotations, pathways, CPIC guidelines, and FDA-approved drug
labels. <br /></div><div><br /></div><div>Drugs with newly available summaries include:</div><div><ul style="text-align: left;"><li><a href="https://www.pharmgkb.org/chemical/PA448691" target="_blank">Busulfan</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449014" target="_blank">Cisplatin</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449027" target="_blank">Cladribine</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449211" target="_blank">Dapsone</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449412" target="_blank">Doxorubicin</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449552" target="_blank">Etoposide</a></li><li><a href="https://www.pharmgkb.org/chemical/PA165980614" target="_blank">Fluindione</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449686" target="_blank">Fluticasone propionate</a></li><li><a href="https://www.pharmgkb.org/chemical/PA449748" target="_blank">Gemcitabine</a></li><li><a href="https://www.pharmgkb.org/chemical/PA164749431" target="_blank">Gemtuzumab ozogamicin</a></li><li><a href="https://www.pharmgkb.org/chemical/PA10804" target="_blank">Imatinib</a></li><li><a href="https://www.pharmgkb.org/chemical/PA450085" target="_blank">Irinotecan</a></li><li><a href="https://www.pharmgkb.org/chemical/PA450163" target="_blank">Lamivudine</a><br /></li></ul></div><div>PharmGKB continues to add to the list of drugs with pediatric summaries. To browse all drugs with available pediatric summaries, please check out the <a href="https://www.pharmgkb.org/pediatric/dashboard" target="_blank">PharmGKB Pediatric Dashboard</a>.<br /></div><p> </p>Clarissa Kleinhttp://www.blogger.com/profile/09156878508940884587noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-69243918904250690022023-12-20T16:21:00.000-08:002023-12-20T16:25:08.155-08:00Updates to Drug Label Annotation Tags and Criteria for PGx levels<p><span><span style="font-family: arial;"><span style="white-space-collapse: preserve;">PharmGKB has made some changes in the </span><a href="https://www.pharmgkb.org/labelAnnotations" style="white-space-collapse: preserve;" target="_blank">Drug Label Annotation</a><span style="white-space-collapse: preserve;"> process to clarify the pharmacogenomic (PGx) relationships of biomarkers. PharmGKB curates all drug labels on the FDA’s <a href="https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling" target="_blank">Table of Pharmacogenomic Biomarkers in Drug Labeling</a> and previously attempted to classify all labels with <a href="https://www.pharmgkb.org/page/drugLabelLegend#pgx-level" target="_blank">PharmGKB-created “PGx levels” </a>. However many of the relationships do not fit standard pharmacogenomic definitions. It is clear from over a decade of label curation that many labels, including many on the FDA Biomarker list, mention genes, variants, chromosomal rearrangements, testing, drug-drug interactions and other incidental information but do not explicitly provide pharmacogenomic clinical guidance or information. Accordingly, we have altered the PGx level definition for “Informative PGx”, and created a new PGx level “Criteria Not Met” and a new drug label annotation tag "Indication”. </span></span></span></p><p><span><span style="font-family: arial;"><span style="white-space-collapse: preserve;">PharmGKB also attempts to identify and curate drug labels from other regulatory agencies for drugs with annotated FDA labels. Labels from other regulatory agencies may or may have similar information to the FDA-approved label, but sometimes the label cannot be found after a search. Previously, if a label was not found, the entry on the <a href="https://www.pharmgkb.org/labelAnnotations" target="_blank">Drug Label Annotations Landing page</a> was left blank. However, if a search has not yet been done, the entry is also blank, which led to ambiguity. PharmGKB now states when a label is not found. </span></span></span><span style="background-color: white; color: #1f1f1f; font-family: arial; white-space-collapse: preserve;"> </span></p><span id="docs-internal-guid-e832c25d-7fff-9c6b-543e-b2d0c88eb4ff"><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">The main changes we are implementing are:</span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">1. to define where the testing requirement is part of the indication of the drug.</span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">The<b> Indication </b>tag is<b> </b></span><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">defined as “The gene or variant is an Indication for the drug, or the drug is for use in a specific population defined by the gene or variant(s), according to the label.” There are many anti-cancer drug examples of this including </span><a href="https://www.pharmgkb.org/chemical/PA166246421" style="text-decoration-line: none;" target="_blank"><span style="background-color: white; color: #2a74df; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space-collapse: preserve;">adagrasib</span></a><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"> and </span><a href="https://www.pharmgkb.org/chemical/PA165981154" style="text-decoration-line: none;" target="_blank"><span style="background-color: #f6f7f8; color: #1952a4; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space-collapse: preserve;">afatinib</span></a>, <span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">and currently 128 out of 182 indication-tagged drug labels regard variants and genes in the cancer genome. Additional non-cancer examples are </span><span style="background-color: white; color: #222222; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">alglucosidase alfa, a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease</span><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">, and d</span><span style="background-color: white; color: #222222; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">esmopressin, a synthetic vasopressin analog that is FDA approved to increase plasma levels of factor VIII activity in patients with hemophilia </span><span style="background-color: white; color: #222222; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">A (</span><a href="https://www.pharmgkb.org/gene/PA27952" style="text-decoration-line: none;" target="_blank"><span style="background-color: white; color: #2a74df; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space-collapse: preserve;">F8</span></a><span style="background-color: white; color: #222222; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"> </span><span style="background-color: white; color: #222222; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">deficiency) and von Willebrand’s disease Type I. </span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">2. to update the criteria for "informative PGx" level and to indicate where the information on the label does not meet our criteria for pharmacogenomics with tag "Criteria not met". Previously, these would have been lumped into “Testing required” and “Informative PGx” tags, respectively. </span></span></p><span style="font-family: arial;"><br /></span><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">The<b> Informative PGx </b>level is now defined as<b> </b></span><span style="background-color: white; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"> “The label contains information stating that particular gene/protein/chromosomal variants or metabolizer phenotypes do NOT affect a drug’s efficacy, dosage, metabolism or toxicity. Or, the label states that particular variants or phenotypes affect a drug’s efficacy, dosage, metabolism or toxicity, but this effect is NOT “clinically” significant”.</span></span></p><span style="font-family: arial;"><br /></span><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">The<b> Criteria not met l</b>evel is defined as "the</span><span style="white-space-collapse: preserve;"> labels appear or appeared on the </span><a href="https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling" style="white-space-collapse: preserve;" target="_blank">FDA Biomarker List </a><span style="white-space-collapse: preserve;">but do not currently meet the </span><a href="https://www.pharmgkb.org/page/drugLabelLegend#pgx-level" style="white-space-collapse: preserve;" target="_blank">requirements</a></span><span style="white-space-collapse: preserve;"><span style="font-family: arial;"> to be assigned as “Testing required”, “Testing recommended”, “Actionable PGx” or “Informative PGx”. PharmGKB annotates every label that appears on the FDA Biomarker list, regardless of whether we would otherwise annotate the label. PharmGKB also checks European Medicines Agency (EMA), and Health Canada/Santé Canada (HCSC) databases for the same drug label and annotates them if they contain pharmacogenomics information and applies the PGx level tags as appropriate.”</span></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQLT9XO4Lorjzy1u2sclYDi07Gp7lsUd-qTD_quOh3GaUxdk-pNGy3ZuYgfy7deUHn1x-jgXucu2yKb5rwBKbYJZG7V2v_OOkUpjeu8R-7_kZibitEFdEHKSIUaORfO0wlTHlqJtxkN_bTPlH0VbjsDfDepSD9eGfLzz4zbhhugw2iRJ9KrozhvRwJ5tsx/s2362/Screenshot%202023-12-14%20at%202.13.17%20PM.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="924" data-original-width="2362" height="224" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQLT9XO4Lorjzy1u2sclYDi07Gp7lsUd-qTD_quOh3GaUxdk-pNGy3ZuYgfy7deUHn1x-jgXucu2yKb5rwBKbYJZG7V2v_OOkUpjeu8R-7_kZibitEFdEHKSIUaORfO0wlTHlqJtxkN_bTPlH0VbjsDfDepSD9eGfLzz4zbhhugw2iRJ9KrozhvRwJ5tsx/w573-h224/Screenshot%202023-12-14%20at%202.13.17%20PM.png" width="573" /></a></div><br /><div class="separator" style="clear: both; font-family: Arial, sans-serif; font-size: 11pt; text-align: center;"><br /></div></span><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">An example that changed from "informative PGx" to "criteria not met" is</span></span><span style="font-family: arial; white-space-collapse: preserve;"> </span><a href="https://www.pharmgkb.org/labelAnnotation/PA166159963" style="font-family: arial; white-space-collapse: preserve;" target="_blank">blinatumomab</a><span style="font-family: arial; white-space-collapse: preserve;">, which is listed on the FDA table of biomarkers with BCR-ABL and CD19. The mechanism of action is via CD19 but the label does not have information on variants of CD19 and any changes in efficacy or toxicity. The label includes information on clinical studies that included patients with Philadelphia chromosome negative Refractory B-cell Precursor ALL.</span></p><span style="font-family: arial;"><br /></span><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">Example where labels language is different across the different agencies:</span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">Lomitapide (</span><a href="https://www.pharmgkb.org/chemical/PA166114922/labelAnnotation" style="text-decoration-line: none;"><span style="color: #1155cc; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space-collapse: preserve;">https://www.pharmgkb.org/chemical/PA166114922/labelAnnotation</span></a><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">) - FDA and HCSC criteria not met, EMA testing required.</span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">Mavacamten (</span><a href="https://www.pharmgkb.org/chemical/PA166272922/labelAnnotation" style="text-decoration-line: none;"><span style="color: #1155cc; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space-collapse: preserve;">https://www.pharmgkb.org/chemical/PA166272922/labelAnnotation</span></a><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">) - FDA and HCSC label for Mavacamten has actionable PGx whereas the EMA label requires CYP2C19 genotyping. </span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;">3. To show when a search was performed for the label but the curator was unable to find the document at the stated repository. </span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="white-space-collapse: preserve;">Entries in the <a href="https://www.pharmgkb.org/labelAnnotations" target="_blank">Drug Label Annotations</a> landing page now show “<b>No document available</b>” if a label could not be found. See an example screen shot from the landing page below.</span></span><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhkUZnHfOPM3NYQ2OjFp7Xh_AVsNoVWbnBSvZFbSLZzU11Qvi4AnNL_5o6MHlfBjjEAtK8FPph6QiDJoe-xhhth6bOVh2t0_8mQ0d8yn6T_8mIA1toEUtEHJ9tL6CH1R7S8E2-V1XkAq8_vitdsF1-xgnzjdWwWzGX6bDHO0FjM0ode7KSrpDTzpYRe3RUT/s1400/Screenshot%202023-12-14%20at%202.17.51%20PM.png" style="clear: left; display: inline; margin-bottom: 1em; margin-right: 1em; text-align: center;"><img border="0" data-original-height="368" data-original-width="1400" height="121" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhkUZnHfOPM3NYQ2OjFp7Xh_AVsNoVWbnBSvZFbSLZzU11Qvi4AnNL_5o6MHlfBjjEAtK8FPph6QiDJoe-xhhth6bOVh2t0_8mQ0d8yn6T_8mIA1toEUtEHJ9tL6CH1R7S8E2-V1XkAq8_vitdsF1-xgnzjdWwWzGX6bDHO0FjM0ode7KSrpDTzpYRe3RUT/w458-h121/Screenshot%202023-12-14%20at%202.17.51%20PM.png" width="458" /></a></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><br /></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="white-space-collapse: preserve;"><span style="font-family: arial;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="white-space-collapse: preserve;"><span style="font-family: arial;">4. To enable accession to the label source directly for FDA and EMA labels. </span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="white-space-collapse: preserve;"><br /></span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="white-space-collapse: preserve;">At the bottom of the drug label annotation page, there is a section titled “<b>Source</b>” that has a link to download the drug label that is the source of the information in the annotation. This label is typically also available in the body of the annotation. The downloadable PDF file is usually highlighted with relevant PGx and drug-drug interaction information. See an example screen shot from the <a href="https://www.pharmgkb.org/labelAnnotation/PA166104833" target="_blank">label annotation for abacavir</a> below.</span></span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><span style="white-space-collapse: preserve;"><br /></span></span></p><span style="font-family: arial;"><span style="white-space-collapse: preserve;"><span style="font-family: arial;"><img border="0" data-original-height="210" data-original-width="1328" height="75" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiy6id8J59-ydmEfq8LNnNLTSKhLyUCqYTmbLlUwe-0zEiDR5aFgmq1ElxdI60bRw4Y25KSWsORVfZb9YNO0pqs1hLQfNSOhWAbtDn-iIwSjKv9Z_okBgFI1R4B4A193wCzMLktY4TAovCHn4Mxzq7__FWkslelb5spwMOmVfqZiLzBjMrghEz-1Fpli1rV/w474-h75/Screenshot%202023-12-14%20at%202.19.48%20PM.png" width="474" /></span></span></span><div><span style="font-family: arial;"><span style="white-space-collapse: preserve;"><br /></span></span></div><div><span style="font-family: arial;"><span style="white-space-collapse: preserve;">When we began annotating FDA-approved drug labels over a decade ago, we did not anticipate how widespread the use of our label annotation tags would become. Many groups have published papers that discuss PGx and FDA labels using the relative numbers of our tags (e.g. PMIDs 26693845, 25317785, 25521333, 29205206, 29722046, 34412102, 28073152). In 2012 we had 113 label annotations from the FDA; we now have over a thousand label annotations across global sources. As stated in our </span><a href="https://pharmgkb.blogspot.com/2013/11/fda-approved-drug-labels.html" style="white-space-collapse: preserve;" target="_blank">blog from 2013</a><span style="white-space-collapse: preserve;">, “Curators have tried to define clearly how they interpret the level of PGx information on labels, resulting in definitions that are really a rather long list of criteria. These definitions may change over time as new label wording comes up and definitions need to adjust for these new cases.” Indeed, the PGx level definitions have been tweaked over the years to accommodate the unique nuances of labels encountered during the curation process, and we continually work to apply the changes across labels from the FDA and then cross-check against other international regulatory bodies, such as the EMA and HCSC.
We are pleased that the community had found our label annotations useful and strive to improve and expand the annotations for future use. We hope these updates make the drug label annotations more consistent and evidence more transparent. Please contact us at feedback@pharmgkb.org with questions</span></span><span style="font-family: arial; white-space-collapse: preserve;">. <br /></span><br /></div>Li Gonghttp://www.blogger.com/profile/07379068611119375369noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-30223755057008174692023-12-18T10:50:00.000-08:002023-12-21T16:38:25.756-08:00CPIC Guideline for Potent Volatile Anesthetic Agents and Succinylcholine - RYR1 variant updateThe original guideline, supplement, and the supporting gene and drug files are available on the <a href="https://cpicpgx.org/guidelines/cpic-guideline-for-ryr1-and-cacna1s/" target="_blank">CPIC website</a>. Annotations of the guideline, including an interactive genotype picker tool are available on the <a href="https://www.pharmgkb.org/guidelineAnnotation/PA166303941" target="_blank">PharmGKB website</a>.<div><br /></div><div>Subsequent to the publication of the CPIC Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of <i>RYR1</i> or <i>CACNA1S</i> Genotypes (<a href="https://files.cpicpgx.org/data/guideline/publication/volatile_anesthetic_succinylcholine/2018/30499100.pdf" target="_blank">PMID 30499100</a>), the ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility (<a href="https://pubmed.ncbi.nlm.nih.gov/35849058/" target="_blank">PMID 35849058</a>). CPIC has added an additional 291 variants and updated the RYR1 <a href="https://files.cpicpgx.org/data/report/current/allele_definition/RYR1_allele_definition_table.xlsx" target="_blank">allele definition</a>, <a href="https://files.cpicpgx.org/data/report/current/frequency/RYR1_frequency_table.xlsx" target="_blank">frequency</a>, and <a href="https://files.cpicpgx.org/data/report/current/allele_function_reference/RYR1_allele_functionality_reference.xlsx" target="_blank">functionality</a> tables accordingly (additional details can be found in the notes tab of the RYR1 allele functionality table). <div><br /></div><div>Pathogenic and likely pathogenic variants are assigned a CPIC function of Malignant Hyperthermia associated, variants of uncertain significance (VUS) are mapped to uncertain function, and benign and likely benign variants are assigned normal function. </div><div><br /></div><div>Additionally, CPIC has created a <a href="https://files.cpicpgx.org/data/report/current/diplotype_phenotype/RYR1_Diplotype_Phenotype_Table.xlsx" target="_blank">RYR1 diplotype to phenotype</a> table. RYR1 phenotypes are determined based on the function combinations of two <i>RYR1</i> variants. The RYR1 diplotype to phenotype table contains all possible combinations of two <i>RYR1</i> variants included in the RYR1 allele functionality file. In case >2 variants are found, the variants with Malignant Hyperthermia associated function should be used first. If 2 Malignant Hyperthermia associated variants are found, those are assumed on different chromosomes.</div><div><br /></div><br /><div><br /></div><div><br /></div></div>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-21922277567627734262023-11-27T10:32:00.000-08:002023-11-27T10:32:07.745-08:00New Fluoropyrimidine Toxicity Variants Reported in DPYS and PPARD<p><span face="Arial, Helvetica, sans-serif" style="background-color: white; color: #222222; font-size: small;">A recent paper highlights new variants and genes a</span>ssociated with severe fluoropyrimidine-related toxicity in patients who were genotyped as negative for the four DPYD variants the European Medicines Agency recommends testing for.</p><span face="Arial, Helvetica, sans-serif" style="background-color: white; color: #222222; font-size: small;">Online ahead of print in the Human Genomics journal is De Mattia et al "The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity" [<a href="https://www.pharmgkb.org/literature/15150472/overview" target="_blank">PMID: 37946254</a>].</span><div><br /></div><div>The study sequenced 120 patients with fluoropyrimidine induced grade 3-5 toxicity confirming they lacked DPYD*2A, DPYD*13, c.2846A > T, c.1236G > A-HapB3. The paper reports rare and common variants including DPYS rs143004875-T and PPARD rs2016520-T which were associated with increased risk of severe toxicity.</div>Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-43261111290378559092023-11-09T09:21:00.001-08:002023-11-09T13:36:20.277-08:00Save the Date: ClinPGx 2024 Meeting<p><span style="font-family: Calibri, sans-serif; font-size: 11pt;">In collaboration with </span><b style="font-family: Calibri, sans-serif; font-size: 11pt;">CPIC</b><span style="font-family: Calibri, sans-serif; font-size: 11pt;">, </span><b style="font-family: Calibri, sans-serif; font-size: 11pt;">PharmGKB</b><span style="font-family: Calibri, sans-serif; font-size: 11pt;">, PharmCAT and PharmVar, the University of Pennsylvania, Penn Center for Precision Medicine will be hosting the </span><b style="font-family: Calibri, sans-serif; font-size: 11pt;">ClinPGx 2024: Knowledge, Implementation, Education</b><span style="font-family: Calibri, sans-serif; font-size: 11pt;"> meeting June 20</span><sup style="font-family: Calibri, sans-serif;">th</sup><span style="font-family: Calibri, sans-serif; font-size: 11pt;"> and 21</span><sup style="font-family: Calibri, sans-serif;">st</sup><span style="font-family: Calibri, sans-serif; font-size: 11pt;">, 2024 in Philadelphia, PA. The meeting will provide educational content to cover all aspects of PGx implementation including knowledgebases, implementation strategies, informatics, use of AI in precision medicine, clinical laboratory insights, and more. Additional details to soon.</span></p>Teri Klein, Co-PI PharmGKB, CPIC, PharmCAT & ClinGenhttp://www.blogger.com/profile/11747692512953774031noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-79304339568467086772023-09-26T08:58:00.002-07:002023-09-26T12:00:52.430-07:00Frequencies of Pharmacogenomic Alleles across UK Biobank Biogeographic Groups Published<div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">We are happy to announce the publication of our latest research article in the American Journal of Human Genetics (AJHG), titled “Frequencies of Pharmacogenomic Alleles across Biogeographic Groups in a Large-Scale Biobank.” The paper is now available online on the <a href="https://authors.elsevier.com/a/1hp%7EbgeX6L46">AJHG website</a>.</div><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">Genetic biobanks provide rich data sets to investigate population-specific pharmacogenomic (PGx) allele frequencies and the implications of equitable and inclusive implementation. Using an integrated UK Biobank 200K genetic dataset (N = 200,044), we estimated the pharmacogenomic (PGx) allele frequencies for seventeen (17) pharmacogenes in five (5) biogeographic groups. </div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;"><ul style="text-align: left;"><li>Pharmacogenes included <i>ABCG2, CACNA1S, CYP2B6, CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, G6PD, IFNL3, NUDT15, RYR1, SLCO1B1, TPMT, UGT1A1, </i>and<i> VKORC1</i>. <i>CFTR</i> and the <i>CYP2C</i> cluster variant (rs12777823) were also investigated. <i>CYP2D6</i> alleles that could be determined from VCF, and therefore not including structural variants, were also predicted.</li><li>The five (5) biogeographic groups are Europeans (n = 187,660), Central/South Asians (n = 3,460), East Asians (n = 637), African Americans/Afro-Caribbeans (n = 1,926), and Sub-Saharan Africans (n = 1,235)</li><li>Frequencies of PGx alleles, diplotypes, phenotypes, and/or activity scores, if applicable, were reported for each gene in each biogeographic group.</li></ul></div></div></blockquote><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">We found that 100% of the UK Biobank participants harbored at least one genetic variant found in known PGx haplotypes. </div><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">The main takeaways messages are:</div><div class="separator" style="clear: both;"><br /></div></div><blockquote style="border: none; margin: 0px 0px 0px 40px; padding: 0px; text-align: left;"><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">1.<span style="white-space: pre;"> </span>UK Biobank PGx frequencies complemented the CPIC frequency tables.</div></div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;"><br /></div></div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">2.<span style="white-space: pre;"> </span>This study reported frequencies for a nontrivial number of PGx alleles that are rare or seldom tested, especially in the non-European group.</div></div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;"><br /></div></div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;">3.<span style="white-space: pre;"> </span>There are uncataloged PGx alleles.</div></div></blockquote><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">PGx frequencies estimated from this study will be disseminated via PharmGKB. Biobank-derived allele frequencies can provide guidance for future PGx studies and clinical genetic test panel design, and better serve individuals from wider biogeographic backgrounds.</div><div class="separator" style="clear: both;"><br /></div></div><div><br /></div>Binglan Lihttp://www.blogger.com/profile/08207707001424607298noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-77206805724521072182023-09-25T08:15:00.001-07:002023-09-25T08:16:17.649-07:00Disulfiram Pathway published in Pharmacogenetics and Genomics<p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEizb6_DRE2UqciByVQusq2BgBaF_STyeibcgkmULEQPYOzPnXLUXhp4Uc4aJAYkXPnKtWvAQELu043lF9OUpGYnA726_iY9NWmuE9BRj5LpRcBk2ZvZPQihX1iSNi_vz0UtTM2ox2ElYmhc7RnSBE55V482-NOr_jvrECSpYKzT7SVn-2HTCED0lBAu060u/s778/Screen%20Shot%202023-09-22%20at%205.17.56%20PM.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="564" data-original-width="778" height="232" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEizb6_DRE2UqciByVQusq2BgBaF_STyeibcgkmULEQPYOzPnXLUXhp4Uc4aJAYkXPnKtWvAQELu043lF9OUpGYnA726_iY9NWmuE9BRj5LpRcBk2ZvZPQihX1iSNi_vz0UtTM2ox2ElYmhc7RnSBE55V482-NOr_jvrECSpYKzT7SVn-2HTCED0lBAu060u/s320/Screen%20Shot%202023-09-22%20at%205.17.56%20PM.png" width="320" /></a></div><br />Substance abuse disorders are a significant public health cost [PMID: 34453125]. Prescribers have limited choices for pharmaceutical therapies with only three FDA-approved choices for alcohol use disorder and zero for cocaine use disorder. Disulfiram is an FDA-approved treatment for alcohol use disorder which is also used for cocaine use disorder. There are some preliminary studies on the PGx of disulfiram but little replication.<p></p><p>PharmGKB together with Dr Aneysis De Las Mercedes Gonzalez (Stanford University School of Medicine), have published PharmGKB summary: disulfiram pathway in Pharmacogenetics and Genomics, 2023 Sep 21. doi: 10.1097/FPC.0000000000000509. Online ahead of print. <a href="https://pubmed.ncbi.nlm.nih.gov/37728645/" target="_blank">PMID: 37728645.</a> It summarizes the candidate genes involved in disulfiram PGx in pharmacokinetics and action in dopaminergic, seratonergic and noradrenergic neurons and highlights the knowledge gaps.</p><p>As always interactive versions of the diagrams with underlying linked evidence, are available on PharmGKB:</p><p><a href="https://www.pharmgkb.org/pathway/PA166287601" target="_blank">Disulfiram Pathway, Pharmacokinetics</a>,</p><p><a href="https://www.pharmgkb.org/pathway/PA166287721" target="_blank">Disulfiram Pathway, Pharmacodynamics (Cocaine and Ethanol PK)</a>, </p><p><a href="https://www.pharmgkb.org/pathway/PA166287741" target="_blank">Disulfiram Pathway, Pharmacodynamics (Dopaminergic neuron)</a>, </p><p><a href="https://www.pharmgkb.org/pathway/PA166287781" target="_blank">Disulfiram Pathway, Pharmacodynamics (Serotonergic neuron)</a>, </p><p><a href="https://www.pharmgkb.org/pathway/PA2042" target="_blank">Sympathetic Nerve Pathway (Neuroeffector Junction)</a></p>Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-77825156068353123752023-08-18T22:54:00.010-07:002023-08-18T22:59:08.772-07:00Please Take This Survey If Your Site Conducts DPYD Genetic Testing Prior to Fluoropyrimidine Chemotherapy<p><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;">Dan Hertz (</span><a href="mailto:DLHertz@med.umich.edu" style="background-color: white; color: #1155cc; font-family: "Helvetica Neue"; font-size: 14px;" target="_blank"><span class="il">DLHertz@med.umich.edu</span></a><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;">) and the</span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;"> </span><i style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;">DPYD</i><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;"> </span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 14px;">Implementation Team </span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;">are collecting information from sites and clinicians in the USA that</span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;"> </span><u style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;"><b>conduct <i>DPYD</i> genetic testing prior to fluoropyrimidine chemotherapy treatment</b></u><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;">. If this applies to you, please complete this brief (<5 minutes) survey on behalf of your site before mid-September. This information will be used to develop best practice guidelines for pre-treatment</span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;"> </span><i style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;">DPYD</i><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;"> </span><span style="background-color: white; font-family: "Helvetica Neue"; font-size: 10.5pt;">testing. </span></p><p class="MsoNormal" style="background-color: white; color: #222222; font-family: Arial, Helvetica, sans-serif; font-size: small; margin: 0px;"><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; color: #32363a; font-family: "Helvetica Neue"; font-size: 12.5pt;"><a data-saferedirecturl="https://www.google.com/url?q=https://umich.qualtrics.com/jfe/form/SV_9Fjv2HdyQ6K6MU6&source=gmail&ust=1692133426388000&usg=AOvVaw3RKOqZ9NPzXTXOuBMdu-XJ" href="https://umich.qualtrics.com/jfe/form/SV_9Fjv2HdyQ6K6MU6" style="color: #1155cc;" target="_blank">https://umich.qualtrics.com/<wbr></wbr>jfe/form/SV_9Fjv2HdyQ6K6MU6</a></span><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; font-family: "Helvetica Neue"; font-size: 12.5pt;"><u></u><u></u></span></p><p class="MsoNormal" style="background-color: white; color: #222222; font-family: Arial, Helvetica, sans-serif; font-size: small; margin: 0px;"><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; font-family: "Helvetica Neue"; font-size: 10.5pt;"><u></u> <u></u></span></p><p class="MsoNormal" style="background-color: white; color: #222222; font-family: Arial, Helvetica, sans-serif; font-size: small; margin: 0px;"><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; color: black; font-family: "Helvetica Neue"; font-size: 10.5pt;">Thanks for your participation!</span><span style="background-attachment: initial; background-clip: initial; background-image: initial; background-origin: initial; background-position: initial; background-repeat: initial; background-size: initial; font-family: "Helvetica Neue"; font-size: 10.5pt;"><u></u><u></u></span></p><p class="MsoNormal" style="background-color: white; color: #222222; font-family: Arial, Helvetica, sans-serif; font-size: small; margin: 0px;"><br /></p>Michelle Whirl-Carrillo, Director and Co-PIhttp://www.blogger.com/profile/00763934303746375004noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-23143720101367273032023-07-13T11:30:00.003-07:002023-07-13T11:36:24.177-07:00New AMP testing recommendations for alleles in CYP3A4 and CYP3A5<p><br /></p><p></p><span style="font-family: arial;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiM6ek5OY-59OjpyeUaDCiodHac_w5lOwr_8MA6Ugj35XfSKW0nX_LiqKE4GLoZeeSC2eLUTGGkhry3-is5NSmldTU8pVR8EOvz5gPJUzVMZH8vXRzOodXip3dVttLrx4mfq2Xg4G6rk6DrWB-MM0NVGAMEk8vwjsbwCDW5SF8cwKjyf2iHkQMmlQWmRnOH/s1964/Screen%20Shot%202023-07-12%20at%202.32.45%20PM.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em; text-align: right;"><img border="0" data-original-height="766" data-original-width="1964" height="159" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiM6ek5OY-59OjpyeUaDCiodHac_w5lOwr_8MA6Ugj35XfSKW0nX_LiqKE4GLoZeeSC2eLUTGGkhry3-is5NSmldTU8pVR8EOvz5gPJUzVMZH8vXRzOodXip3dVttLrx4mfq2Xg4G6rk6DrWB-MM0NVGAMEk8vwjsbwCDW5SF8cwKjyf2iHkQMmlQWmRnOH/w407-h159/Screen%20Shot%202023-07-12%20at%202.32.45%20PM.png" width="407" /></a></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div>The Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase have jointly published recommendations on what constitutes the minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) for CYP3A4 and CYP3A5 [PMID</span><span style="font-family: arial;">:<a href="https://preview.pharmgkb.org/literature/15146130">337419245</a>].</span><div><br /><div><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj3VY49GxN3Ojh2uoXNx5X3TsZQl86w7vI9ooCJDR-M_k4TBRzZBHUQKIYeM2QTZKw_sa_Wa2pAj8NAE2bdLkwOZxZvin70u266ymQQV8am91_InwEoai3j6Ln65F7mQWI6l5UMg8fL0iJBVRegghrPTfBMc5zoPuhIZ8ssAMqlc0XS8iy2o_GXxpVxqict/s1860/Screen%20Shot%202023-07-12%20at%202.31.19%20PM.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="80" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj3VY49GxN3Ojh2uoXNx5X3TsZQl86w7vI9ooCJDR-M_k4TBRzZBHUQKIYeM2QTZKw_sa_Wa2pAj8NAE2bdLkwOZxZvin70u266ymQQV8am91_InwEoai3j6Ln65F7mQWI6l5UMg8fL0iJBVRegghrPTfBMc5zoPuhIZ8ssAMqlc0XS8iy2o_GXxpVxqict/w400-h80/Screen%20Shot%202023-07-12%20at%202.31.19%20PM.png" width="400" /></a></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;">Tier 1 <a href="https://www.pharmgkb.org/haplotype/PA166048680" target="_blank">CYP3A4*22</a>, <a href="https://www.pharmgkb.org/haplotype/PA166128219" target="_blank">CYP3A5*3</a>, <a href="https://www.pharmgkb.org/haplotype/PA166128233" target="_blank">CYP3A5*6</a>, <a href="https://www.pharmgkb.org/haplotype/PA166128234" target="_blank">CYP3A5*7</a></span></div><div><span style="font-family: arial;">Tier 2 <a href="https://www.pharmgkb.org/haplotype/PA165819244" target="_blank">CYP3A4*20</a></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;">PharmGKB maintains the lists for these alleles and the tier 1 and tier 2 alleles previously published for CYP2C19, CYP2C9, VKORC1, TPMT. NUDT15 at <a href="https://www.pharmgkb.org/ampAllelesToTest">https://www.pharmgkb.org/ampAllelesToTest</a><br /><br /><br /></span></div><div><span style="font-family: arial;">When on an allele page there is a tag to show if this allele is part of the recommended test set:</span></div><div><div class="separator" style="clear: both; text-align: left;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhbrLpEAMJHQW9mWIyOJQqZ1ueOfp2QG6uMCU0NvWl8e3uNw37X-KJ_mw4x7DYsol2WSZEH-Ox0F7qcZHm_m-XGfW9W2yO8pUxpWJ6TmXHQqz575SMBnNhQ26tRexA4e0WtllXEAKlZ-Nc1fTzfTWFfmQh1g8UDAT_60FNuxemt__Sc9ROJEeZj6j5I44Dm/s1262/Screen%20Shot%202023-07-13%20at%201.46.16%20PM.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="734" data-original-width="1262" height="135" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhbrLpEAMJHQW9mWIyOJQqZ1ueOfp2QG6uMCU0NvWl8e3uNw37X-KJ_mw4x7DYsol2WSZEH-Ox0F7qcZHm_m-XGfW9W2yO8pUxpWJ6TmXHQqz575SMBnNhQ26tRexA4e0WtllXEAKlZ-Nc1fTzfTWFfmQh1g8UDAT_60FNuxemt__Sc9ROJEeZj6j5I44Dm/w232-h135/Screen%20Shot%202023-07-13%20at%201.46.16%20PM.png" width="232" /></a></div><br /><span style="font-family: arial;"><br /></span><div class="separator" style="clear: both; text-align: left;"><span style="font-family: arial;">When on a gene page there is a tag to show the gene has an AMP set of test alleles plus there is a link to the AMP page from the VIP summary. </span></div><div class="separator" style="clear: both; text-align: left;"><span style="font-family: arial;"><br /></span></div><div class="separator" style="clear: both; text-align: left;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjrEqBUWFQmFye65XA0TL8RRrnKhL4iMHjzEFkiSMZJDCe3_GxYXAdm8W0T1AQ1sRQkQDea3pGMagfrJ2wnn6u5F2-6JPlRc10l9AZSF8PomhhxlCsjoSGeS4y69YEX7xg1I7ZGyty1ecoZzF1_Ddsir6-uQe1vMQw5hNd7BWYrBMcbiBRy_UVGwnXuUoau/s2266/Screen%20Shot%202023-07-13%20at%202.28.37%20PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="1190" data-original-width="2266" height="168" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjrEqBUWFQmFye65XA0TL8RRrnKhL4iMHjzEFkiSMZJDCe3_GxYXAdm8W0T1AQ1sRQkQDea3pGMagfrJ2wnn6u5F2-6JPlRc10l9AZSF8PomhhxlCsjoSGeS4y69YEX7xg1I7ZGyty1ecoZzF1_Ddsir6-uQe1vMQw5hNd7BWYrBMcbiBRy_UVGwnXuUoau/s320/Screen%20Shot%202023-07-13%20at%202.28.37%20PM.png" width="320" /></a></div><br /><span style="font-family: arial;"><br /></span></div><br /><p><br /></p><p><br /></p><p><br /></p><p><br /></p></div></div>Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-73518330026224978122023-07-12T10:34:00.002-07:002023-07-12T11:35:33.681-07:00Insights on CYP2C19 and phenoconversion<br /><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">Phenoconversion in the PGx context is a drug-drug interaction that impacts a drug metabolizing phenotype such that it mimics the effects of a metabolizer genotype (see <a href="https://pharmgkb.blogspot.com/2022/10/there-is-no-ontology-term-for.html" target="_blank">blog from October 2022</a>). Historically much of the discussion on phenoconversion has focused on CYP2D6.</span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">A new paper in Frontiers in Pharmacology investigates the phenoconversion effects of different CYP2C19 inhibitors [PMID:<a href="https://www.pharmgkb.org/literature/15145744" target="_blank">37361233</a>]. </span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">Forty donor liver samples were genotyped for CYP2C19 *2, *3 and *17 and the metabolizer phenotypes predicted. Microsomes were assayed with the probe drug s-mephenytoin and then in the presence of strong CYP2C19 inhibitor fluvoxamine, moderate inhibitors omeprazole and voriconazole and weak inhibitor pantoprazole to look at changes in metabolizer status. </span></p><p class="p2" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px; min-height: 15px;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbAk67CdSnxYDJSnM_jZ81fZPP_Gk2d49zEhpQam3oAJ9WvQB_zjmgX_LmssiesPFW82UHtYFrpa0vs_YJi2gkDpaR5LuGT8GPOdgYPCXn6sVheKNNTnzDZji-pl_aJpdVhFDVhZNRLIBw5hFw4bgTMp4VhMRDQMHX262ZrQdKxh3L-jv8vzHrmrb6W4la/s372/Screen%20Shot%202023-07-12%20at%201.29.05%20PM.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="font-family: arial;"><img border="0" data-original-height="204" data-original-width="372" height="63" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbAk67CdSnxYDJSnM_jZ81fZPP_Gk2d49zEhpQam3oAJ9WvQB_zjmgX_LmssiesPFW82UHtYFrpa0vs_YJi2gkDpaR5LuGT8GPOdgYPCXn6sVheKNNTnzDZji-pl_aJpdVhFDVhZNRLIBw5hFw4bgTMp4VhMRDQMHX262ZrQdKxh3L-jv8vzHrmrb6W4la/w116-h63/Screen%20Shot%202023-07-12%20at%201.29.05%20PM.png" width="116" /></span></a></div><span style="font-family: arial;"><br /></span><p></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">Excerpts from paper:</span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">“Our results demonstrate that the outcome of a DDI is dictated by both inhibitor strength and CYP2C19 activity, which is in turn dependent on genotype and non-genetic factors including comorbidities. … </span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"></p><p class="p1" style="font-family: "Helvetica Neue"; font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;">Fluvoxamine, a strong inhibitor of CYP2C19, caused 86% of *1/*17 donors to become phenotypically IM, whereas most of genetically-predicted IMs were converted to a PM phenotype (57%). In accordance with unaltered CYP2C19 activity in patients with gastroesophageal reflux disease taking pantoprazole, weak inhibition by pantoprazole did not induce phenoconversion…</p><p class="p1" style="font-family: "Helvetica Neue"; font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">However, the outcomes of DDIs with moderate inhibitors (omeprazole/voriconazole) matched less well to the proposed phenoconversion model by Mostafa et al, which predicted that NMs/IMs convert to a PM phenotype upon moderate inhibition of CYP2C19. In our study, voriconazole, which acts as a moderate CYP2C19 inhibitor, significantly reduced the drug metabolizing capabilities of CYP2C19 by approximately one level (i.e., from a phenotypic NM to a IM). As a result, 40% of the donors (12/30) were converted into IM or PM phenotypes by voriconazole. Though, none of the NMs were converted into PMs, except for one donor who already exhibited impaired CYP2C19 activity in the absence of voriconazole treatment (basal phenoconversion). For omeprazole, phenoconversion into IM or PM phenotypes was even less frequently seen, in only 10% of the donors …</span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">Altogether, our data suggest that CYP2C19 inhibition by moderate inhibitors can result in phenoconversion, but it seems unlikely to result into a PM phenotype for wild-type *1/*1 genotypes.”</span></p><p class="p2" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px; min-height: 15px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">There are a number of interesting results and discussion points:</span></p><p class="p2" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px; min-height: 15px;"><span style="font-family: arial;"><br /></span></p><ul class="ul1"><li class="li1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><span class="s1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 9px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal;"></span>There is phenoconversion from disease phenotype - namely diabetes. </span></li><li class="li1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><span class="s1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 9px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal;"></span>The initial concordance for genotype to phenotype with s-mephenytoin was only 40% and the two CYP2C19*17/*17 did not have ultra-rapid UM phenotype (with Vmax in the low normal NM range). The discussion mentions “other (rare) genetic variants within CYP2C19 could also have influenced the mismatch between predicted and observed activities in our study” but it would have been useful to have ruled out *4. The *17/*17 did produce functional mRNA but the *4 is in the start codon and its impact is on translation not transcription [PMID: 9435198]. </span></li><li class="li1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><span class="s1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 9px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal;"></span>There were two *1/*1 outliers with very high UM phenotype that would be interesting to see further genetic analysis of especially given the escitalopram UM CYP2C-haplotype defined by rs2860840T and rs11188059G in [PMID: 33759177]. </span></li></ul><p class="p2" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px; min-height: 15px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;">Overall, this paper shows that while phenoconversion exists for CYP2C19 based on disease status and DDIs, the impact is not a simple downgrading of phenotype (e.g. from IM to PM) that can be applied in a consistent manner across subjects. The authors show that even for strong inhibitors, phenoconversion happens in 40%-86% of subjects with no clear way to predict which subjects would experience phenoconversion and which wouldn’t. More research on how DDIs alter patient-predicted genotype to phenotype is needed to enable better prediction of patient phenotype for PGx drug dosing recommendations.</span></p><p class="p1" style="font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><span style="font-family: arial;"><br /></span></p><p class="p1" style="font-family: "Helvetica Neue"; font-feature-settings: normal; font-kerning: auto; font-optical-sizing: auto; font-size: 13px; font-stretch: normal; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-variation-settings: normal; line-height: normal; margin: 0px;"><br /></p><p></p>Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-2154954764547866702023-06-26T10:13:00.005-07:002023-06-26T10:13:56.677-07:00ClinGen Pharmacogenomics Working Group (PGxWG) Survey To Close Soon<p> </p><p><span face=""Arial",sans-serif" style="background: white; color: black;">The </span><a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank"><span face=""Arial",sans-serif" style="background: white;">ClinGen Pharmacogenomics Working Group (PGxWG)</span></a>'s anonymous<span face=""Arial",sans-serif" style="background: white; color: black;"> </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span face=""Arial",sans-serif" style="background: white;">survey</span></a> will close soon after <b>this Friday, June 30, 2023</b>. Our goal is to gather opinions and<span face=""Arial",sans-serif" style="background: white; color: black;"> feedback
regarding the criteria and terminology that should be used to define
clinical validity and actionability for pharmacogenes and variants. If you have not yet had the chance to fill it out or pass it along, please do so soon! </span></p><p><span face=""Arial",sans-serif" style="background: white; color: black;">Pharmacogenomics expertise is not required - we are also looking for responses across the broader global genetics and medical communities as well (</span><span face=""Arial",sans-serif" style="background: white; color: black;">clinicians, pharmacists, labs, genetic counselors, etc.)</span><span face=""Arial",sans-serif" style="background: white; color: black;"></span><span face=""Arial",sans-serif" style="background: white; color: black;"> All responses are appreciated, no matter who you are or where you are in the world. If you’ve previously
completed the survey, we appreciate your contribution and there's no
need to submit a second response. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif">The survey can be accessed at: </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span face=""Arial",sans-serif">https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4</span></a><span face=""Arial",sans-serif">. We sincerely appreciate your time and participation, and your willingness to help.</span></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAE7y2M6LnGaJHiNdgEccRt40iw7Jsk6ZSGTkXK5tgnNlygmUa1h71VNRK40QalvPcokFVQEW6gQkYX58YvhojqUr1eTMQtQU4q0byDp-aWGLVUNUtoLDgVudwNYB9HZ4op2FLAiLiAsJ7TBURYsJCpRSeHUQyk9NeDM_ymdpbVixcodYA7ggGEQSUQA/s262/QR.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="262" data-original-width="262" height="262" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAE7y2M6LnGaJHiNdgEccRt40iw7Jsk6ZSGTkXK5tgnNlygmUa1h71VNRK40QalvPcokFVQEW6gQkYX58YvhojqUr1eTMQtQU4q0byDp-aWGLVUNUtoLDgVudwNYB9HZ4op2FLAiLiAsJ7TBURYsJCpRSeHUQyk9NeDM_ymdpbVixcodYA7ggGEQSUQA/s1600/QR.png" width="262" /></a></div>Clarissa Kleinhttp://www.blogger.com/profile/09156878508940884587noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-32609706556143548482023-06-09T14:24:00.001-07:002023-06-09T14:24:25.216-07:00ClinPGx Sessions at PGRN 2023 Conference and ClinGen Summer Workshops<p>At the upcoming <a href="https://www.pgrn.org/event-5081449" target="_blank">PGRN 2023 annual conference</a> in Memphis, Dr. Teri E. Klein, the principle investigator for PharmGKB, ClinGen, CPIC and PharmCAT, will hold a town hall discussion on ClinPGx: a single integrated resource for Pharmacogenomics (PGx). Dr. Klein will discuss the challenge of the separation of pharmacogenomic resources from clinical genomic resources, and present a long-term, conceptual framework for broadly integrating the available PGx resources into a single resource, ClinPGx. </p><p>Dr. Klein will also present at the upcoming <a href="https://clinicalgenome.org/tools/clingen-summer-workshop-series-2023/june-16-2023/" target="_blank">ClinGen 2023 Summer Workshop Series on June 16</a> 11am PT. Please come join us. We are actively seeking feedback from the PGx and genomics community on the interest and development of ClinPGx to facilitate the incorporation of PGx into standard of care. Zoom link below: </p><p>June 16th, 2023, 11am PT/ 2pm ET </p><p>Join Zoom Meeting : </p><p><a href="Join Zoom Meeting https://acmg.zoom.us/j/87027015818?pwd=S2U2OTFhQ1oranFZZjNlTEhHN0FlUT09 Meeting ID: 870 2701 5818 Passcode: 83854960 One tap mobile +16699006833,,87027015818# US (San Jose) +17193594580,,87027015818# US " target="_blank">https://acmg.zoom.us/j/87027015818?pwd=S2U2OTFhQ1oranFZZjNlTEhHN0FlUT09 </a></p><p>Meeting ID: 870 2701 5818 </p><p>Passcode: 83854960 </p><p>One tap mobile </p><p>+16699006833,,87027015818# US (San Jose) </p><p>+17193594580,,87027015818# US </p><div><br /></div>Li Gonghttp://www.blogger.com/profile/07379068611119375369noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-80735686188376439802023-06-09T10:56:00.000-07:002023-06-09T10:56:27.625-07:00ClinGen Pharmacogenomics Working Group (PGxWG) Survey Open Until June 30, 2023<p><span face=""Arial",sans-serif" style="background: white; color: black;">The </span><a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank"><span face=""Arial",sans-serif" style="background: white;">ClinGen Pharmacogenomics Working Group (PGxWG)</span></a>'s anonymous<span face=""Arial",sans-serif" style="background: white; color: black;"> </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span face=""Arial",sans-serif" style="background: white;">survey</span></a> is <b>OPEN until June 30, 2023</b>. Our goal is to gather opinions and<span face=""Arial",sans-serif" style="background: white; color: black;"> feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. Please help disseminate to ALL (clinicians, pharmacists, labs, genetic counselors, etc.). We are looking for BROAD global participations - please send to your friends and colleagues too! If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif">The survey can be accessed at: </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span face=""Arial",sans-serif">https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4</span></a><span face=""Arial",sans-serif">. We sincerely appreciate your time and participation, and your willingness to help.</span></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAE7y2M6LnGaJHiNdgEccRt40iw7Jsk6ZSGTkXK5tgnNlygmUa1h71VNRK40QalvPcokFVQEW6gQkYX58YvhojqUr1eTMQtQU4q0byDp-aWGLVUNUtoLDgVudwNYB9HZ4op2FLAiLiAsJ7TBURYsJCpRSeHUQyk9NeDM_ymdpbVixcodYA7ggGEQSUQA/s262/QR.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="262" data-original-width="262" height="262" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAE7y2M6LnGaJHiNdgEccRt40iw7Jsk6ZSGTkXK5tgnNlygmUa1h71VNRK40QalvPcokFVQEW6gQkYX58YvhojqUr1eTMQtQU4q0byDp-aWGLVUNUtoLDgVudwNYB9HZ4op2FLAiLiAsJ7TBURYsJCpRSeHUQyk9NeDM_ymdpbVixcodYA7ggGEQSUQA/s1600/QR.png" width="262" /></a></div><br /><span face=""Arial",sans-serif"><br /></span><p></p>Li Gonghttp://www.blogger.com/profile/07379068611119375369noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-8858317012083502762023-05-10T13:46:00.006-07:002023-05-11T09:37:49.619-07:00Announcement of PharmVar Content Changes<p><span style="font-family: helvetica;"><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;"><a href="https://www.pharmvar.org/">PharmVar</a> continues to evolve and strive to offer high-quality content to our global users. To allow us to bring new clinically relevant content to PharmVar we needed to make some difficult decisions and ‘retire’ several</span><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;"> </span><i style="caret-color: rgb(34, 34, 34); color: #222222;">CYP</i><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;"> </span><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;">genes. This decision is based on a newly developed points-based rating system (0-100 points) that allows us to prioritize which genes to maintain and which genes to evaluate for future introduction into PharmVar. More detailed information regarding PharmVar gene content and prioritization will be posted under the</span><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;"> </span><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmvar.org/genes&source=gmail&ust=1683825374805000&usg=AOvVaw30QpMNvlFzAE1MYWYoHPxL" href="https://www.pharmvar.org/genes" style="caret-color: rgb(34, 34, 34); color: #1155cc;" target="_blank">GENES</a><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;"> </span><span face="Arial, Helvetica, sans-serif" style="caret-color: rgb(34, 34, 34); color: #222222;">tab once these changes have taken effect May 12, 2023.</span></span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); margin: 0px;"><span style="font-family: helvetica;"><span style="color: #222222;">The following genes were not considered pharmacogenes by PharmVar due to their contribution to </span>lipid and steroid metabolism and/or associations with <span style="color: #222222;">disease and will be retired</span><span style="background-color: white; color: #222222;">: </span><i style="background-color: white; color: #222222;"><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27118/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0f-iQXV-8zzyZPNWEfma1e" href="https://www.pharmgkb.org/gene/PA27118/clinicalAnnotation" style="color: #1155cc;" target="_blank">CYP4A11</a>, CYP4A22, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27119/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw39EzYCmzk6W8y01n9HHmxZ" href="https://www.pharmgkb.org/gene/PA27119/clinicalAnnotation" style="color: #1155cc;" target="_blank">CYP4B1</a>, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27090/variantAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw3Z-O3mpA5m-5QZzDkK15IQ" href="https://www.pharmgkb.org/gene/PA27090/variantAnnotation" style="color: #1155cc;" target="_blank">CYP17A1</a>, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27091/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw2SeXEzMzdfMOKFJYnAC2r4" href="https://www.pharmgkb.org/gene/PA27091/clinicalAnnotation" style="color: #1155cc;" target="_blank">CYP19A1</a>, CYP21A2</i><span style="background-color: white; color: #222222;">, </span><i style="background-color: white; color: #222222;">CYP26A1</i><span style="background-color: white; color: #222222;">, </span><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA349/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0Yk1-mx4yZhl20AINmOmOC" href="https://www.pharmgkb.org/gene/PA349/clinicalAnnotation" style="background-color: white; color: #1155cc;" target="_blank"><i>TBXAS1</i> </a><span style="color: #222222;"> and </span><i style="color: #222222;">PTGIS </i><span style="color: #222222;">(0 points each</span>), <span style="background-color: white;">though several of these genes have variant and low level clinical annotations on PharmGKB</span>. Ot<span style="color: #222222;">her databases such as <a href="https://clinicalgenome.org/" target="_blank">ClinGen</a> and/or <a href="https://www.ncbi.nlm.nih.gov/clinvar/" target="_blank">ClinVar</a> may also be consulted for variation annotations. These genes were listed by PharmVar as ‘legacy’ gene</span><span style="color: #222222;">s. </span><i style="background-color: white; color: #222222;"><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA33532/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw1dI8InLqMmuiXN0FSqwClv" href="https://www.pharmgkb.org/gene/PA33532/clinicalAnnotation" style="color: #1155cc;" target="_blank">POR</a></i><span style="background-color: white; color: #222222;"> </span><span style="color: #222222;">(3 points)</span><span style="color: #222222;"> was also listed as a legacy gene. The following genes were transitioned into the PharmVar database, but never curated by an expert panel nor any add</span><span style="color: #222222;">itional data added: </span><i style="color: #222222;">CYPs </i><i style="background-color: white; color: #222222;"><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27092/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0YXR8B2b2LGd2K_QUHeGrN" href="https://www.pharmgkb.org/gene/PA27092/clinicalAnnotation" style="color: #1155cc;" target="_blank">1A1</a></i><i style="background-color: white; color: #222222;">, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27094/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw1NeWDq2VUev4nXnEbYyFsH" href="https://www.pharmgkb.org/gene/PA27094/clinicalAnnotation" style="color: #1155cc;" target="_blank">1B1</a>, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA129/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw1JBXGVrNSZBqoU7CWNnLlr" href="https://www.pharmgkb.org/gene/PA129/clinicalAnnotation" style="color: #1155cc;" target="_blank">2E1</a>, 2F4, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA27112/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0MNKH_j3dXMoidhzqKW2Uk" href="https://www.pharmgkb.org/gene/PA27112/clinicalAnnotation" style="color: #1155cc;" target="_blank">2J2</a>, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA134986407/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0A61hW7_VkHvoI5qCP7o7h" href="https://www.pharmgkb.org/gene/PA134986407/clinicalAnnotation" style="color: #1155cc;" target="_blank">2R1</a>, 2S1,</i><span style="background-color: white; color: #222222;"> </span><i style="background-color: white; color: #222222;">2W1, <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA122/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw1K9RmwCkyt50F_BH1x-GGK" href="https://www.pharmgkb.org/gene/PA122/clinicalAnnotation" style="color: #1155cc;" target="_blank">3A7</a> </i><span style="background-color: white; color: #222222;">and </span><i style="background-color: white; color: #222222;"><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA427/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0Jip_BX9g4Sbh8QBtuhXmc" href="https://www.pharmgkb.org/gene/PA427/clinicalAnnotation" style="color: #1155cc;" target="_blank">3A43</a></i><i style="background-color: white; color: #222222;">.</i><span style="background-color: white; color: #222222;"> </span><span style="color: #222222;">These genes were not deemed to be clinically important pharmacogenes by the PharmVar Steer</span><span style="color: #222222;">ing Committee based on having 0 points in the ranking system and will also be retired. Furthermore, the link to the archived Human Cytochrome P450 (CYP) Allele Nomenclature database record (last version by </span>cypalleles.ki.se<span style="color: #222222;"> in 2017) will be deactivated to discourage use of outdated information (a copy can be requested through </span><a href="mailto:support@pharmvar.org" style="color: #1155cc;" target="_blank">support@pharmvar.org</a><span class="m_3700789590706764954MsoHyperlink" style="color: #0563c1; text-decoration-line: underline;">)</span><span style="color: #222222;">.</span></span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; margin: 0px;"><span style="font-family: helvetica;">If new data emerges and rankings change, a gene may be reintroduced to PharmVar. <u></u><u></u></span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; margin: 0px;"><i><span style="font-family: helvetica;"><u></u> <u></u></span></i></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); margin: 0px;"><span style="font-family: helvetica;"><i style="color: #222222;"><a href="https://www.pharmgkb.org/gene/PA18" target="_blank">NAT2</a></i><span style="color: #222222;"> is currently undergoing curation and is anticipated to be transferred from the </span><a data-saferedirecturl="https://www.google.com/url?q=http://nat.mbg.duth.gr/&source=gmail&ust=1683825374805000&usg=AOvVaw0cXJQvm3IbilRftCvG9Yu_" href="http://nat.mbg.duth.gr/" style="color: #1155cc;" target="_blank">Databases of Arylamine N-acetyltransferases (NATs)</a><span style="color: #222222;"> to PharmVar in summer 2023. The introduction of </span><i style="color: #222222;">NAT2</i><span style="color: #222222;"> into the PharmVar database is timely as CPIC is initiating a guideline for the </span><i style="color: #222222;">NAT2</i><span style="color: #222222;">/hydralazine gene-drug pair. <u></u><u></u></span><span style="background-color: white;">Additionally, NAT2 has <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA18/clinicalAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw0VXRWONbmJJJmmlik1fhDY" href="https://www.pharmgkb.org/gene/PA18/clinicalAnnotation" style="color: #1155cc;" target="_blank">multiple clinical annotations</a><span style="color: #222222;"> and </span><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/gene/PA18/labelAnnotation&source=gmail&ust=1683874399566000&usg=AOvVaw1haHrWYfCpX6BTaRJHJFn5" href="https://www.pharmgkb.org/gene/PA18/labelAnnotation" style="color: #1155cc;" target="_blank">mulitple annotated FDA and other regulatory agency labels</a></span><span style="background-color: white; color: blue;">.</span></span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; margin: 0px;"><span style="font-family: helvetica;"><u></u> <u></u></span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; margin: 0px;"><span style="font-family: helvetica;">As always, PharmVar values your feedback and suggestions <a href="mailto:support@pharmvar.org" style="color: #1155cc;" target="_blank">support@pharmvar.org</a>.</span></p>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-37223789488972879072023-05-01T05:33:00.001-07:002023-05-01T05:33:13.087-07:00CYP3A5 genotyping is a more accurate predictor of drug response than race alone<p> <span style="font-family: Arial; font-size: 11pt; white-space: pre-wrap;">A <a href="https://www.pharmgkb.org/literature/15143270" target="_blank">new paper in Journal of Clinical Pharmacology</a> from a group at Indiana University [PMID:37042314] implemented genotyping for CYP3A5 in a kidney transplant center.</span></p><span id="docs-internal-guid-a81b9f5f-7fff-ba42-7ae2-43522b6802d5"><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">The team used CPIC guidelines for tacrolimus dosing based on CYP3A5 genotype.</span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">Implementation included provider education and clinical decision support in the electronic medical record.</span></p><br /><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">This study reinforces that CYP3A5 genotype is an important predictor of therapeutic tacrolimus trough concentrations. They demonstrate that CYP3A5 normal and intermediate metabolizers had fewer tacrolimus trough concentrations within the desired range post-transplantation and took longer to achieve therapeutic dose than poor metabolizers. While the authors note they were underpowered to measure outcomes, there was a trend towards transplant rejection or all-cause mortality within the first year of transplant based on CYP3A5 metabolizer phenotype.</span></p><br /><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">The paper highlights how, despite the <a href="https://www.pharmgkb.org/guidelineAnnotation/PA166124619" target="_blank">guidelines from CPIC</a> being published in 2015, the FDA label still currently only has language around race-based dose adjustment rather than giving precise guidance based on genotype:</span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">“The FDA drug label recommends higher starting doses in individuals of African ancestry, but only 70% of African Americans are normal/intermediate metabolizers. CYP3A5 normal/intermediate metabolizers are also found among whites and Asians (East Asian and Central/South Asian) at lower frequencies (14% and 44-55%, respectively).”</span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">“Self-reported African American race is more closely associated with CYP3A5 expresser status than other self-reported race categories, but self-reported race is not an accurate surrogate for genotype.”</span></p><br /><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">The discussion is a reminder that pharmacogenomics can play a key role in reducing bias and fulfilling personalized precision medicine.</span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">“Equality and minimization of bias in healthcare has recently become prioritized by healthcare systems as recognition of racial bias has come to the forefront in many non-healthcare aspects of society”</span></p><p dir="ltr" style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt;"><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">“One dose standard protocols and using race as a surrogate for genotype can both potentiate racial disparities in tacrolimus dosing. Routine CYP3A5 genotyping is a more accurate predictor of drug response than race alone and deemphasizes race as a biological variable in clinical care”</span></p><div><span style="font-family: Arial; font-size: 11pt; font-variant-alternates: normal; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><br /></span></div></span>Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-4250791996704711422023-04-13T10:09:00.000-07:002023-04-13T10:09:14.629-07:00CPIC Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4 and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants<p><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">The</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><a data-saferedirecturl="https://www.google.com/url?q=https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/&source=gmail&ust=1681488048646000&usg=AOvVaw0bcczEOgCfthEos0swoyRK" href="https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/" style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;" target="_blank">CPIC guideline</a><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">for</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2D6</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">,</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2C19</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">,</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2B6</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">,</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">SLC6A4</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">and</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">HTR2A</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> genotypes and Serotonin Reuptake Inhibitor Antidepressants has been published in the journal</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"><a data-saferedirecturl="https://www.google.com/url?q=https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.2903&source=gmail&ust=1681488048646000&usg=AOvVaw1auQDrsw1_sYa6un7GrjnR" href="https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.2903" target="_blank">Clinical Pharmacology and Therapeutics</a></i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">. This</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">new</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">guideline</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">updates the CPIC guideline for Selective Serotonin Reuptake Inhibitors and</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2D6 </i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">and </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2C19</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">, and</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">includes</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">additional Serotonin Reuptake Inhibitor Antidepressants and three additional genes,</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">CYP2B6</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">,</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">HTR2A</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">, and</span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span><i style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">SLC6A4</i><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">. </span><span style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"> </span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif; margin: 0px;"><u></u></p><div style="caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"><span class="im"><p class="MsoNormal" style="margin: 0px;"><br />The guideline gives specific prescribing recommendations for:<u></u><u></u></p><ul style="margin-bottom: 0in;" type="disc"><li class="MsoNormal" style="margin: 0px 0px 0px 15px;">paroxetine, fluvoxamine, venlafaxine, and vortioxetine based on CYP2D6 phenotypes<u></u><u></u></li><li class="MsoNormal" style="margin: 0px 0px 0px 15px;">escitalopram and citalopram based on CYP2C19 phenotypes<u></u><u></u></li><li class="MsoNormal" style="margin: 0px 0px 0px 15px;">sertraline based on CYP2C19 and CYP2B6 phenotypes</li></ul><div><br /></div></span><div><p class="MsoNormal" style="margin: 0px;"><span class="im">Clinical recommendations are not provided for serotonin reuptake inhibitor antidepressants based on <i>HTR2A</i> and <i>SLC6A4</i> genotypes because the current evidence is mixed and/or insufficient to support clinical validity and utility.<br /> <br /></span>For specific recommendations and further details, please refer to the guideline and supplemental materials on the <a data-saferedirecturl="https://www.google.com/url?q=https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/&source=gmail&ust=1681488048646000&usg=AOvVaw0bcczEOgCfthEos0swoyRK" href="https://cpicpgx.org/guidelines/cpic-guideline-for-ssri-and-snri-antidepressants/" target="_blank">CPIC website</a>. Annotations of the guideline, including an interactive genotype picker tool for the drugs mentioned above, are available on the <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/&source=gmail&ust=1681488048646000&usg=AOvVaw19lAxK6d7lVcphwpLKRjoN" href="https://www.pharmgkb.org/" target="_blank">PharmGKB website</a>.</p></div></div>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-9480213999365992852023-04-10T06:34:00.000-07:002023-04-10T06:34:31.286-07:00It’s national poetry month again!<p style="text-align: left;"><br />I am not a mouse.<br />It’s the reference allele<br />(hg38).</p><br />I am not a mouse.<br />It's the common variant<br />In these folks tested. <br /><br /><br />Saw on minus strand<br />G is the major allele<br />In this group tested. <br /><br /><br />C is the minor <br />It’s the reference allele<br />(hg38).<br /><br /><br />Last year I wrote a haiku to highlight my gripe about authors declaring a patient a *1 but not stating which alleles were tested so not conclusively ruling out the presence of variants. This year I have a series of haiku on another gripe of mine - authors using the term “wild-type” when talking about humans. I’ve been guilty of it in the past but when we know better we do better. The one upside of it is it's a way one can avoid using terms major/minor allele when those might be different in different populations and thus ambiguous, but I think most study participants would not want to be categorized as wild-type, certainly most would not want to be called mutant (unless it comes with some X-men type powers). The terms I would recommend are “reference allele/genotype” (on genome build …) and “comparison allele/genotype”. If using major/minor allele then state explicitly what base that was in the given population, and describe the population, and which strand the allele was measured on (especially for C/G and A/T variants and genes on minus chromosomal strand). We have been seeing problems lately when authors assume the reference allele on the genome build hg38 is the major allele in most populations and that is not always the case. If in doubt give as much information as possible.Caroline Thorn, Curatorhttp://www.blogger.com/profile/04350901252906154243noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-60677368305613531282023-03-20T12:45:00.001-07:002023-03-20T12:45:14.165-07:00CYP2D6 allele function update<p><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;">The CYP2D6 allele functionality file has been re-evaluated and updated by experts involved in CYP2D6-related CPIC guidelines. CYP2D6 functions are now assigned up to star allele 163. </span></p><div style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"><div>Part of the re-evaluation focused on alleles that include 100C>T (P34S) (*10 key SNP). Furthermore, the activity value of several decreased function alleles, e.g. *9 and *41, was downgraded to 0.25. </div><div><br /></div><div>The updated file can be accessed through CYP2D6-related guidelines on the <a data-saferedirecturl="https://www.google.com/url?q=https://cpicpgx.org/guidelines/&source=gmail&ust=1679421631509000&usg=AOvVaw1vx0Cu7a5J3rgrz9FerzUw" href="https://cpicpgx.org/guidelines/" style="color: #1155cc;" target="_blank">CPIC</a> website and through the CYP2D6 resource page on <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmgkb.org/page/cyp2d6RefMaterials&source=gmail&ust=1679421631509000&usg=AOvVaw0cv7XlGd-uQvFQq49HIs9H" href="https://www.pharmgkb.org/page/cyp2d6RefMaterials" style="color: #1155cc;" target="_blank">PharmGKB</a>. The updated functions are also displayed on the <a href="https://www.pharmvar.org/gene/CYP2D6" target="_blank">PharmVar</a> CYP2D6 page .</div></div>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-32591087466416926032023-03-13T09:55:00.001-07:002023-03-13T09:55:32.660-07:00ClinGen Pharmacogenomics Working Group (PGxWG) Follow-Up Survey<p><span style="font-size: small;"><span style="background: white; color: black; font-family: "Arial",sans-serif;">The </span><a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank"><span style="background: white; font-family: "Arial",sans-serif;">ClinGen
Pharmacogenomics Working Group (PGxWG)</span></a><span style="background: white; color: black; font-family: "Arial",sans-serif;"> has just launched a second </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span style="background: white; font-family: "Arial",sans-serif;">survey </span></a><span style="background: white; color: black; font-family: "Arial",sans-serif;">to solicit
feedback about the criteria and terminology that should be used to define
clinical validity and actionability for pharmacogenes and variants from both
the PGx community and the wider genetics and medical communities. Please note
that this second survey is <b>not independent of the first, </b>and if you’ve
taken the previous survey and have significant PGx familiarity or expertise,
there is no need to take this iteration, as it would be redundant due to the
overlap in questions.</span></span>
</p><p class="MsoNormal"><span style="font-size: small;"><span style="font-family: "Arial",sans-serif;">The </span><a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank"><span style="font-family: "Arial",sans-serif;">ClinGen PGxWG</span></a><span style="font-family: "Arial",sans-serif;"> is a multi-disciplinary team of
researchers and professionals with expertise in pharmacogenomics (PGx),
clinical pharmacology, medical genetics, regulatory affairs, and molecular
diagnostics. It was launched in February 2022 with the goal of developing a
framework of tiered standard terminology and definitions that reflect clinical
significance for genes and genomic variants implicated in drug response, in
order to facilitate the incorporation of PGx knowledge into </span><a href="https://clinicalgenome.org/" target="_blank"><span style="font-family: "Arial",sans-serif;">ClinGen</span></a><span style="font-family: "Arial",sans-serif;">
and more consistent interpretation of PGx variants identified by panel testing
and/or sequencing.</span></span></p>
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: "Arial",sans-serif;">The survey is open now and can be
accessed at: </span><a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4" target="_blank"><span style="font-family: "Arial",sans-serif;">https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4</span></a><span style="font-family: "Arial",sans-serif;">. All responses are greatly appreciated,
no matter who you are or where you are in the world. <b>Unlike the previous
survey, </b>this survey does not assume PGx familiarity, though if you have <b>not</b>
taken the previous survey and have PGx familiarity, your feedback is still
greatly appreciated. The survey takes approximately 15 minutes to complete. We
sincerely appreciate your time and attention, and your willingness to help.</span></span></p>
<p></p>Clarissa Kleinhttp://www.blogger.com/profile/09156878508940884587noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-40221192855157838502023-02-06T08:31:00.001-08:002023-02-06T08:37:33.494-08:00ClinGen Pharmacogenomics Working Group (PGxWG) Survey<p></p><div class="separator" style="clear: both; text-align: center;"><br /></div><span style="background-color: white;"><span style="font-family: arial;">The <a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank">ClinGen Pharmacogenomics Working Group (PGxWG)</a> has launched a <a href="https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM" target="_blank">survey</a> to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. </span></span><div><span style="font-family: arial;"><br /></span></div><div><span style="font-family: arial;"><div>The <a href="https://clinicalgenome.org/working-groups/pharmacogenomics/" target="_blank">ClinGen PGxWG</a> is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into <a href="https://clinicalgenome.org/" target="_blank">ClinGen</a> and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.</div><div><br /></div><div>The survey is open now and can be accessed at: <a contenteditable="false" href="https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM" style="caret-color: rgb(0, 0, 0); color: blue; font-family: Calibri, sans-serif; font-size: 10pt;" target="_blank" title="https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM">https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM</a><span face="Calibri, sans-serif" style="caret-color: rgb(0, 0, 0); font-size: 10pt;">. </span>All responses are greatly appreciated, no matter who you are or where you are in the world. This survey does assume some PGx familiarity, though we plan to launch another survey targeting those with less PGx experience in the near future. The survey takes approximately 10 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.</div></span></div>Li Gonghttp://www.blogger.com/profile/07379068611119375369noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-1229450243893269702023-01-26T11:15:00.000-08:002023-01-26T11:15:26.707-08:00PharmVar updates for CYP3A4 star allele definitions<p> <span style="background-color: white; caret-color: rgb(34, 34, 34); font-family: Calibri, sans-serif;">PharmVar announces several updates for </span><span style="background-color: white; caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;"><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmvar.org/gene/CYP3A4&source=gmail&ust=1674793093516000&usg=AOvVaw3I3-2k4D20RL1WHij1Vmxl" href="https://www.pharmvar.org/gene/CYP3A4" style="color: #1155cc;" target="_blank"><i><span style="font-family: Calibri, sans-serif;">CYP3A4</span></i></a></span><span style="background-color: white; caret-color: rgb(34, 34, 34); font-family: Calibri, sans-serif;"> star allele definitions.</span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif; margin: 6pt 0px 0px;">Retirement of the <i>CYP3A4*1G</i> allele: this allele was defined by a common variant in intron 10 (<span style="background-color: white; color: black;">c.1026+12G>A) which was also found on many other</span> haplotypes (or star alleles). PharmVar <a name="m_-2927861386286433240__Hlk125111077">transiently </a>designated the <i>CYP3A4*1G </i>allele as <i>*36</i> due to a possible role of c.1025+12G>A being involved in the regulation of CYP3A4 expression<span style="color: black;">. However, </span>owing to the growing body of inconsistent findings regarding associations of <span style="background-color: white; color: black;">c.1026+12G>A and higher or lower expression levels and/or CYP3A4 activity,</span> PharmVar withdrew this redesignation in January 2023 (v5.2.17) which led to the retirement of the <i><span style="background-color: white; color: black;">CYP3A4*36</span></i><span style="background-color: white; color: black;"> (former <i>*1G</i>) allele. Per PharmVar rules, intronic variants are only utilized for star allele definitions if </span>there is convincing evidence that the variant impacts protein function<span style="background-color: white; color: black;">. Therefore, c.1026+12G>A was also removed from all other star allele definitions</span>.<u></u><u></u></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif; margin: 6pt 0px 0px;"><i>CYP3A4</i> gene regulation is complex and appears to be governed by a layer of processes, among them long noncoding RNAs, microRNAs and transcription factors which may also influence CYP3A5 activity. Furthermore, there is substrate overlap between CYP3A4 and CYP3A5 and thus, variation in the <i>CYP3A5</i> gene, further complicates the characterization of <i>CYP3A4</i> allele function. Investigators are encouraged to include <span style="background-color: white; color: black;">c.1026+12G>A in their carefully designed investigations to produce conclusive evidence regarding the functional impact of c.1026+12G>A. </span> <u></u><u></u></p><p style="background-color: white; caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"><span style="color: black; font-family: Calibri, sans-serif;">We would also like to highlight the addition of a novel star allele, <i>CYP3A4*38</i> which is characterized by two variants which on their own define <i>CYP3A4*3</i> and <i>*11</i>. Noteworthy, the <i>CYP3A4*3</i>-defining variant c.1334T>C (p.M445T) has also been found together with the intronic SNP defining <i>CYP3A4*22; </i>this allele was designated <i>CYP3A4*37</i>. Consequently, samples heterozygous for these SNPs could have <i>CYP3A4*1/*37</i> or <i>*3/*22</i> or *<i>1/*38</i> or *<i>3/*11 </i>genotypes, respectively. Since the functional impact of c.1334T>C (p.M445T) remains elusive it is unknown whether alternate genotypes differ in function.</span><span style="font-family: Calibri, sans-serif;"><u></u><u></u></span></p><p style="background-color: white; caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"><span style="color: black; font-family: Calibri, sans-serif;">Lastly, the evidence level of several alleles has been updated from ‘Limited’ or ‘Moderate’ to ‘Definitive’ indicating that these alleles are now fully characterized. </span><span style="font-family: Calibri, sans-serif;"><u></u><u></u></span></p><p style="background-color: white; caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"><span style="color: black; font-family: Calibri, sans-serif;">These efforts were only possible by the dedicated work of the PharmVar Team and the <i>CYP3A4 </i>gene experts for volunteering their time and expertise.</span></p>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0tag:blogger.com,1999:blog-6521985176416791926.post-1883171004908949522023-01-24T14:42:00.001-08:002023-01-24T14:42:47.925-08:00CYP4F2 is now fully curated by PharmVar <p><span class="il" style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;">CYP4F2</span><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"> </span><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;">contributes to the</span><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"> </span><span style="background-color: white; caret-color: rgb(34, 34, 34); font-family: Arial, Helvetica, sans-serif;">synthesis of cholesterol, steroids and other lipids</span><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;">. It has been shown to regulate</span><span style="background-color: white; caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;"> the bioavailability of vitamin E and vitamin K, a co-factor that is critical to blood clotting. Variations in </span><span style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif;">this important pharmacogene can affect vitamin K levels and thus, the dosing of vitamin K antagonists such as the widely used anticoagulant drug warfarin (CPIC level A and PharmGKB 1A evidence level) among others.</span></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif; margin: 0px;"><u></u></p><p class="MsoNormal" style="caret-color: rgb(34, 34, 34); color: #222222; font-family: Arial, Helvetica, sans-serif; margin: 0px;"><span style="background-color: white;">We are excited to announce that <i><a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmvar.org/gene/CYP4F2&source=gmail&ust=1674685072572000&usg=AOvVaw3bGbX7samwxXfHp7f5HMqJ" href="https://www.pharmvar.org/gene/CYP4F2" style="color: #1155cc;" target="_blank"><span class="il">CYP4F2</span></a></i> is now fully curated by PharmVar and its gene page content reviewed by an international <a data-saferedirecturl="https://www.google.com/url?q=https://www.pharmvar.org/expert-panels&source=gmail&ust=1674685072572000&usg=AOvVaw3QyVyq765o6_6OtZrH-Eep" href="https://www.pharmvar.org/expert-panels" style="color: #1155cc;" target="_blank">expert panel</a>. Furthermore, the PharmVar Team has generated new data to provide a more comprehensive catalog of genetic variation of this gene. Not only have the two previously defined <i><span class="il">CYP4F2</span>*2</i> and <i>*3 </i>now been fully characterized, several other novel haplotypes (or star alleles) have been identified and designated by PharmVar. Notably, the new and relatively commonly observed <i><span class="il">CYP4F2</span>*4</i> allele has both sequence variants that otherwise define <i>*2</i> (c.34T>G, W12G) and <i>*3</i>(c.1297G>A, V433M), respectively while the other three novel star alleles (<i><span class="il">CYP4F2</span>*5, *6</i> and <i>*7</i>) are each characterized by a single amino acid change. Interestingly, <i><span class="il">CYP4F2</span>*5</i> and <i>*6</i> appear to be absent or rare in Asian populations; in contrast, <i>*7</i> seems to be mostly present in African populations and their descendants. These new star alleles may contribute to unexplained variability in daily warfarin dosage requirements in non-White populations. We encourage the research and clinical communities to include this new knowledge in their investigations.</span></p>Katrin Sangkuhlhttp://www.blogger.com/profile/09555892570397023486noreply@blogger.com0