Tuesday, August 8, 2017

Pharmacogenetics/Genomics (PGx) and Depression Featured on NBC News

On August 7th, NBC News aired a segment on how pharmacogenomics can help treat patients with depression. It highlighted the story of Sarah Ellis from Sioux Falls, SD who had trouble finding a combination of antidepressant and anti-anxiety medications that did not induce debilitating adverse effects. She had tried 23 different combinations of antidepressants over the course of several years until her psychiatrist intuited that pharmacogenetic (PGx) testing might help her. When her test results showed that she did carry genetic variants that affected her response to specific classes of medications, her psychiatrist prescribed a specific class of medications and altered her dose - thereby personalizing her medications to her genetics. According to Sarah Ellis: “My energy's been really great," she says. "I feel like I can accomplish what I want to accomplish. This was definitely worth it.”

PharmGKB has been annotating these gene-drug associations since it began in 2000. Using PharmGKB, one can find drug labels annotated with pharmacogenetic information (and genetic testing recommendations if available), pathway summaries and diagrams, and clinically relevant pharmacogenetic summaries for many drugs including those used to treat depression and anxiety. PharmGKB has also contributed to research with the International SSRI Pharmacogenomics Consortium. In addition, it has contributed to the clinical implementation of PGx through the Clinical Pharmacogenetics Implementation Consortium (CPIC), which has published two guidelines (and one update) for PGx-based prescribing and dosing of two commonly prescribed classes of drugs used to treat anxiety and depression: tricyclic antidepressants (TCA) and SSRIs.

Tuesday, August 1, 2017

Curators' Favorite Papers

Medical education in pharmacogenomics—results from a survey on pharmacogenetic knowledge in healthcare professionals within the European pharmacogenomics clinical implementation project Ubiquitous Pharmacogenomics (U-PGx)
Just KS, Steffens M, Swen JJ, Patrinos GP, Guchelaar HJ, Stingl JC.

Ubiquitous Pharmacogenetics (U-PGx) is a pharmacogenetics implementation project across multiple sites, in countries across Europe. Physicians at U-PGx implementation sites were surveyed online about their “knowledge and attitude towards (pharmacogenetics) PGx”,  and the results were published this month in the European Journal of Clinical Pharmacology. The majority of respondents agreed that PGx was important in their current work, although most also responded that they had not ordered a PGx test. Of those that had not, 40% responded that it was not applicable, and 40% did “not have enough knowledge about PGx testing” but of those that had, 91.7% responded that the results were useful. Despite this, a large majority of participants could not correctly interpret a pharmacogenetics test, and favored educational opportunities to improve their understanding of PGx and PGx implementation. 

The article is available here.

The promise of discovering population-specific disease-associated genes in South Asia
Nakatsuka N, Moorjani P, Rai N, Sarkar B, Tandon A, Patterson N, Bhavani GS, Girisha KM, Mustak MS, Srinivasan S, Kaushik A, Vahab SA, Jagadeesh SM, Satyamoorthy K, Singh L, Reich D, Thangaraj K.

A new study in Nature Genetics, which was also the subject of an article in The New York Times, investigates how genetic drift has played a role in establishing recessive, disease-causing mutations within South Asia where approximately ~5000 distinct communities have been identified. The authors devised an algorithm to identify large chromosomal segments that were shared between individual members of a community due to shared ancestry (identity by descent, or IBD) and identified a high prevalence of recessive, disease-causing alleles that were due to founder events among 81 off 263 unique groups. This was verified when allele-frequency differentiation was assessed in 89 unique groups. As a result, even when consanguineous marriage is not practiced, individuals from the same group had a very high probability of being carriers of the same recessive disease causing mutation. One example cited in the study is that of butyrlcholinesterase deficiency among the Vysya community in India. In that case, the muscle relaxants succinylcholine and mivacurium are contraindicated due to the risk of apnea and death. The authors hope that these findings will help to map disease-associated genes similar to what has been done in the Old Order Amish, and that future carrier screening in affected communities may decrease the incidence of recessive Mendelian diseases. 

The study is available here.


More information about butyrylcholinesterase deficiency and succinylcholine is available at PharmGKB.

Sunday, July 23, 2017

The Roles of CYP2C19 and CYP3A4 in Voriconazole Pharmacogenetics

Voriconazole is a triazole antifungal agent used to treat serious fungal infections. It is primarily used in immunocompromised patients, such as those undergoing organ transplantation. CYP2C19 is the primary enzyme responsible for voriconazole metabolism. CYP3A4, CYP3A5 and CYP2C9 also play a role, secondary to CYP2C19. The influence of genetic polymorphisms in CYP2C19 is well documented in clinical studies, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) recently released guideline for voriconazole dosing based on CYP2C19 genotype.

In the August issue of Clinical Pharmacology and Therapeutics, Gautier-Veyret et al wrote a perspective piece discussing two retrospective studies showing that genetic variations in CYP3A4 gene may influence voriconazole trough concentrations, suggesting that in addition to CYP2C19, CYP3A4 should also be genotyped for voriconazole dosing.

In response to this, CPIC guideline authors Walsh et al acknowledged the different opinions on the role of CYP3A4 in voriconazole pharmacokinetics and clarified the reasons why CPIC authors feel there is NOT sufficient evidence to recommend altered voriconazole dosing based on genetic polymorphisms in CYP3A4/CYP3A5.

For further details see both articles in the August edition of Clinical Pharmacology and Therapeutics:

Walsh TJ, Moriyama B, Penzak SR, Klein TE, Caudle KE.
Clin Pharmacol Ther. 2017 Aug;102(2):190. doi: 10.1002/cpt.681. Epub 2017 Apr 29. 
PMID: 28455946

Gautier-Veyret E, Fonrose X, Stanke-Labesque F.
Clin Pharmacol Ther. 2017 Aug;102(2):189. doi: 10.1002/cpt.662. Epub 2017 May 26. 

Friday, July 7, 2017

Curators' Favorite Papers

The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial

Jason L. Vassy, MD, MPH, SM; Kurt D. Christensen, PhD, MPH; Erica F. Schonman, MPH; Carrie L. Blout, MS, CGC; Jill O. Robinson, MA; Joel B. Krier, MD; Pamela M. Diamond, PhD; Matthew Lebo, PhD; Kalotina Machini, PhD; Danielle R. Azzariti, MS, CGC; Dmitry Dukhovny, MD, MPH; David W. Bates, MD, MSc; Calum A. MacRae, MD, PhD; Michael F. Murray, MD; Heidi L. Rehm, PhD; Amy L. McGuire, JD, PhD; and Robert C. Green, MD, MPH for the MedSeq Project

This study, published  in the Annals of Internal Medicine, received a lot of attention in prominent media outlets including Wired, STATNPR, Washington Post and Science Magazine. As part of the MedSeq project, 100 healthy adults were recruited by 9 primary care providers (PCP), themselves briefed on genomics and how to refer patients to genetics experts. All patients gave a detailed family history (FH) but were randomized to get either whole genome sequencing (WGS) (WGS +FH) or not (FH) and were surveyed at 6 months regarding follow-up care and well-being. The study authors uncovered monogeneic disease risk (MDR) variants in 11 patients, but only 2 manifested the phenotype (fundus albipunctatus and subclinical porphyria). 48 of 50 subjects had a pharmacogenetic variant in a gene affecting one of five drugs (warfarin, clopidogrel, simvastatin, metformin, and digoxin) and results were added to electronic health records (EHR). PCPs recommended new clinical actions in 16% and 34% of FH and WGS+ FH patients, respectively. At 6 months, 30% and 41% of patients made health behavior changes in the FH and WGS-FH groups, respectively, but no significant differences in self-reported health, anxiety or depression scores emerged between groups. Overall, the authors conclude that identification of MDR variants did not improve short-term health outcomes, and results do not support the routine use of WGS in healthy patients. However, the authors note that the ability of PCPs to adequately manage patient results, their use of EHR, and their appropriate referrals to genetic specialists, as well as self-reported patient well-being after receiving results are encouraging signs that indicate a favorable environment for WGS in future studies and specific clinical care situations.

You can read the study here and more information about the pharmacogenetics of warfarin, clopidogrel, simvastatin, metformin, and digoxin is available at PharmGKB. 




Wednesday, June 28, 2017

Pharmacogenomics on Nightly News with Lester Holt

The Wednesday, June 28th edition of the Nightly News with Lester Holt featured a short segment on pharmacogenomics.

The piece briefly covered the Mayo Clinic's work in expanding the use of pharmacogenomics in the clinic. Dr. Richard Weinshilboum, co-director of the pharmacogenomics program at the Mayo Clinic, was also interviewed. Dr. Weinshilboum is a leader in the field, and has been a co-author on a number of PharmGKB publications, including multiple PharmGKB pathways and VIPs, as well as the International SSRI Pharmacogenomics Consortium (ISPC) publication. He is also a member of the Pharmacogenomics Research Network (PGRN); PharmGKB is a partner of the PGRN.

PharmGKB provides a page for clinically relevant pharmacogenomic summaries - a list of clinical annotations that contain variant-drug combinations featured in a guideline published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) or other medical society, or implemented at a PGRN site or a major health system, such as the Mayo Clinic. This includes associations such as codeine and CYP2D6 or thiopurine drugs and TPMT; both of these associations have CPIC guidelines. The page also features variant-drug combinations that have a preponderance of evidence showing an association, and therefore may be clinically actionable, but are not currently featured in a guideline.




Tuesday, June 20, 2017

AMIA 10x10 Virtual Pharmacogenomics course with Stanford University begins June 26, 2017

The American Medical Informatics Association (AMIA) has partnered with the Biomedical Informatics program at Stanford University to present an online course in pharmacogenomics (PGx) as part of the AMIA 10 x 10 series. The course, Pharmacogenomics, will  introduce the field and cover topics relevant to PGx including pharmacology, genomics, genome wide association studies (GWAS) and high-throughput assay analyses, natural language processing (NLP), PGx resources such as PharmGKB, Drugbank and NCBI, relevant gene and drug classes as well as current challenges to the implementation of PGx testing in clinical care.  

Russ Altman, MD, PhD, Professor of Bioengineering, Genetics, Medicine, and Computer Science and Director of the Biomedical Informatics Training Program and Co-PI of PharmGKB is also the Director of the 10 x 10 Pharmacogenomics course. Additional instructors include Dr. Michelle Whirl-Carrillo, Associate Director of PharmGKB, Dr. Alison Fohner, former Scientific Curator at PharmGKB, Sara Hillenmeyer, and Dr. Natalia Khuri. 

The course begins June 26th. To learn more and to register, please click here



Tuesday, June 13, 2017

The Next Look for PharmGKB

PharmGKB is excited to show you our all-new website design. We’ve been working hard for months to create a new user interface that serves all of PharmGKB’s content in a clear and flexible way.

You can see the new design by visiting next.pharmgkb.org.

The “next” site uses modern web technologies and frameworks to produce a clear interface no matter which device you’re using. This means mobile & small-screen devices will have a first-class user experience.

We’re using the new api.pharmgkb.org to power this next design. Page load speeds have increased dramatically especially when it comes to our most annotated genes like CYP2D6 and G6PD.

We’d love to know what you think of the new design! Please go to next.pharmgkb.org, use the site, and give us your feedback. Every message you send helps us understand how to help people looking to learn more about pharmacogenomics and precision medicine.

We plan to run next.pharmgkb.org as a preview of things to come while still showing our traditional design at www.pharmgkb.org. After a short trial period we will move the “next” design over to www.pharmgkb.org.

If you have something you’d like us to know about the redesign, please use the feedback button on the bottom-right of any page.


We hope you find this new design as exciting and useful as we do. We look forward to your feedback!