PharmGKB papers in the February 2020 issue of Pharmacogenetics and Genomics

The February 2020 issue of Pharmacogenetics and Genomics has a PharmGKB double feature, with the publication of our sertraline pathway and our VIP summary for CACNA1S.

The sertraline pharmacokinetic pathway, written by Scientific Curator Dr. Rachel Huddart and collaborators, is featured on the cover of the journal. Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is used in the treatment of some psychiatric disorders, such as major depressive disorder. Metabolism of sertraline in the liver by CYP2C19 forms the basis of clinical guidelines from CPIC and the DPWG.

CACNA1S is a subunit of the dihydropyridine receptor and is expressed in skeletal muscle, where it plays a role in muscle contraction. Variants in CACNA1S have been linked to a number of myopathies as well as malignant hyperthermia, which can occur in some patients when exposed to inhaled anesthetics. The recent CPIC guideline forinhaled anesthetics includes recommendations based on CACNA1S variants. Our VIP summary, written by Senior Scientific Curator Dr. Katrin Sangkuhl with Dr.Robert Dirksen of the University of Rochester and former PharmGKB curator Maria Alvarellos, outlines the role of CACNA1S in both normal muscle function and in disease genetics. Key variants which have been associated with malignant hyperthermia are discussed in detail.

Both the sertraline pathway and CACNA1S VIP summary can be accessed on the PharmGKB website.

Very Important Pharmacogene (VIP) summary for MT-RNR1 published in Pharmacogenetics and Genomics

The PharmGKB review of the MT-RNR1 gene has been published in the December issue of Pharmacogenetics and Genomics. MT-RNR1 is a mitochondrial gene that codes for ribosomal RNA (rRNA). Variations within this gene, particularly rs267606617 (1555A>G), are strongly associated with the development of hearing loss following administration of aminoglycoside antibiotics. Indeed, over 40 studies have found that 100% of individuals with the G allele at this variant developed hearing loss after receiving aminoglycosides, a class of antibiotics that includes streptomycin and gentamicin, among others. Several other variations in this gene are also associated with hearing loss following aminoglycoside treatment.

The full Very Important Pharmacogene (VIP) review can also be viewed on the PharmGKB website. In addition to discussing the pharmacogenetics of MT-RNR1, it also provides a brief overview of the mitochondrial genetic system as well as the anatomy of the ear and types of hearing loss.

Introducing the new PharmGKB Cancer PGx Portal

PharmGKB has collected a number of resources for Cancer PGx into one easy location. There are tables with direct links to genes important for cancer drug response both for PD and PK, to cancer drug pathways, particular cancers that have PGx data, types of toxicities common to cancer drugs, and external resources.

Eight new VIP gene pages give a short text based summary of important genes for cancer drug response. These are for the genes ALK, ABL1, BCR, BRAF, ERBB2 (HER2), KIT, KRAS and NRAS. Anyone with expertise in the genes who wishes to develop these with us for publication in PG&G, please contact feedback.

There is a shortlist of drug labels for cancer drugs with biomarker PGx.

We currently have 34 anti-cancer agent drug pathways with 8 new pathways in development. The portal gives shortcuts to a selection.

PharmGKB currently uses a flat ontology for diseases, which means that the Neoplasms disease page does not link to the many different cancers we have data for. The cancer portal has direct links to the cancers for which there is the most PGx information in the knowledgebase, such as pediatric ALL, CML, colorectal, breast, renal and non-small cell lung cancers. The portal also has links to the common types of toxicities with PGx data.

Finally there is a collection of external links that are useful for Cancer PGx.

Very Important Pharmacogene: RYR1

The new Very Important Pharmacogene (VIP) Summary of RYR1 describes important pharmacogenetic associations as well as disease associations with variants in RYR1. RYR1 encodes a single sub-unit of the ryanodine receptor isoform 1 (RYR1), the predominant ryanodine receptor isoform of skeletal muscle. RYR1 is a calcium channel of the sarcoplasmic reticulum of muscle cells (and endoplasmic reticulum in non-muscle cells) and is critical to excitation-contraction coupling, the process by which an electrical signal is translated into a muscle contraction. RYR1 is the primary locus for malignant hyperthermia susceptibility (MHS), a potentially fatal pharmacogenetic condition triggered by volatile anesthetics, alone or in combination with a depolarizing neuromuscular blocking agent, such as succinylcholine. There is limited evidence that variants in RYR1 may also be associated with statin-induced myopathies. The VIP summary also discusses how advances in sequencing have improved MHS diagnoses in otherwise healthy individuals. 

Read the VIP summary below:

https://www.pharmgkb.org/gene/PA34896

PharmGKB VIP summary for CFTR published

The PharmGKB summary describing CFTR as a pharmacogene has been published by Pharmacogenetics & Genomics. Genetic variants within the CFTR gene are the target of new Cystic Fibrosis therapies and drugs in development. The hope is that patients will be better treated with personalized medicines tailored to the underlying defects within CFTR. The VIP summary details these treatment strategies and clinically important variants within the CFTR gene.

• View the interactive online version of the CFTR VIP summary

• Read the article: 

PharmGKB summary: very important pharmacogene information for CFTR. 

McDonagh EM, Clancy JP, Altman RB, Klein TE.   

Pharmacogenetics & Genomics. 2014 Dec 15. (Epub ahead of print)

PharmGKB VIP Summary for CYP4F2 published in Pharmacogenetics and Genomics

The PharmGKB Very Important Pharmacogene (VIP) summary describing important pharmacogenetic variants in CYP4F2 was recently published by Pharmacogenetics & Genomics. Cytochrome p450, family 2, subfamily F, polypeptide 2 (CYP4F2) catalyzes the oxidation of the terminal carbon of the side chains of vitamin K, vitamin E, arachidonic acid (AA), and leukotriene B4 (LTB 4). Thus, CYP4F2 plays a role in the regulation of the inflammation response, blood pressure as well as vitamin K and vitamin E bioavailability. A single genetic variant (rs2108622 C>T also known as CYP4F2 *3) has consistently demonstrated a small but significant effect on warfarin and acenocoumarol dosage and safety, particularly in Caucasian and Asian populations. 

View an interactive version: 

CYP4F2 VIP Summary on PharmGKB


Read the publication:


PharmGKB summary: very important pharmacogene information for CYP4F2 
Pharmacogenetics & Genomics. 2014 Nov 3. (Epub ahead of print)Alvarellos ML, Sangkuhl K, Daneshjou R, Whirl-Carrillo M, Altman RB, Klein TE.

New PharmGKB VIP Summary: HLA-B

Human leukocyte antigen B (HLA-B) is a cell-surface molecule responsible for the presentation of endogenous peptides to cytotoxic CD8+ T cells. This presentation of peptides allows for the recognition of pathogens, and leads to an immune reaction that destroys the infected cell. Variations within the HLA-B gene affect which peptides the molecule can present, but allelic changes have also been associated with susceptibility and resistance to numerous diseases and adverse reactions to a wide range of pharmaceuticals. Some of these pharmaceutical associations have been well-studied, such as HLA-B*57:01 and abacavir hypersensitivity, HLA-B*58:01 and allopurinol-induced severe cutaneous adverse reactions (SCARs), and HLA-B*15:02 and carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, many other variants within the HLA-B gene also show associations with drug phenotypes. 

The VIP summary posted on PharmGKB provides background on HLA-B and its role in the immune system, as well as discussing the roles of HLA-B alleles in diseases and pharmacogenetics, with a particular focus on the *57:01, *58:01 and *15:02 alleles. 

For more information, please read the entire HLA-B VIP summary and its associated variant summaries on PharmGKB.

View all VIP gene summaries at PharmGKB.

New PharmGKB VIP Summary: CYP4F2

Cytochrome p450, family 2, subfamily F, polypeptide 2 (CYP4F2) is known to catalyze multiple biological reactions.  It is predominantly expressed in the liver and kidneys, although there is evidence that it is also expressed in the intestines. Of specific interest in pharmacogenetics, hepatic CYP4F2 regulates the bioavailability of vitamin K and vitamin E and is currently studied to determine how polymorphisms in CYP4F2 affect warfarin dosing in patients. A single variant in CYP4F2 (rs2108622) is significantly associated with small, but significant alterations in warfarin dosage in Asian and Caucasian populations.

For more information on this VIP gene and variant, please see the VIP tab for CYP4F2.

Introducing CFTR as a Very Important Pharmacogene (VIP)

Variants within the CFTR gene underlie Cystic Fibrosis (CF). Traditionally, drugs used in the treatment of this disease have focused on ameliorating symptoms, fighting infection, thinning mucus and dampening inflammation. Now, drug development is focusing on pharmaceuticals that correct the underlying CFTR defect. The PharmGKB CFTR VIP summary describes potential treatment strategies that target defects conferred by particular classes of CFTR variants.

Read VIP information about these CFTR variants: 

• F508del-CFTR is prematurely degraded, failing to reach the plasma membrane. 

          Variants resulting in CFTR gating defects:

• G551D
• S549N
• G1244E 
• G1349D
• G178R
• G551S
• S1251N
• S1255P
• S549R(A>C) and S549R(T>G) 

                                                             

New publication: NAT2 VIP Summary

The PharmGKB Very Important Pharmacogene (VIP) summary for NAT2 has been published in Pharmacogenetics & Genomics.  

The review summarizes the important role NAT2 plays in the metabolism and detoxification of many therapeutic drugs, and why genetic variants within the NAT2 gene are associated with drug-induced toxicity as well as cancer. Associations between drug responses and important NAT2 variants are detailed, and possible reasons behind a lack of consistency for some associations are discussed. 

> View an interactive version of the NAT2 VIP summary on PharmGKB.

> Read the article:

PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2.

McDonagh EM, Boukouvala S, Aklillu E, Hein DW, Altman RB, Klein TE.

Pharmacogenetics & Genomics. 2014 Jun 2. (Epub ahead of print)

NAT2 genetic variants have been linked to drug-induced hepatotoxicity

SLC22A1 VIP Summary Published in PG&G

Solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also called OCT1) is an important drug transporter mediating the hepatic uptake of many commonly used drugs. Several SLC22A1 variants have functional consequences and have been associated with altered disposition and response for drugs such as metformin, imatinib, sorafenib, tropisetron, morphine and tramadol.

We have published the
PharmGKB summary: very important pharmacogene information for SLC22A1 in the Pharmacogenetics and Genomics Journal.

Find out more...
View our SLC22A1 VIP on PharmGKB.

Read our new publication: 
PharmGKB summary: very important pharmacogene information for SLC22A1
Goswami S, Gong L, Giacomini K, Altman RB, Klein TE.
Pharmacogenet Genomics. 2014 Mar 27. [Epub ahead of print]
PMID:24681965

View all VIPs on PharmGKB.