New study reveals PGx knowledge gaps among physicians

A recent study in the journal Pharmacogenomics and Personalized Medicine reveals clear pharmacogenomic “knowledge gaps” among physicians. Katherine A Johansen Taber and Barry D Dickinson of the American Medical Association surveyed 300 physicians across the United States to gauge their familiarity with pharmacogenomics as well as their knowledge of how to order and interpret pharmacogenomic tests.

Only 12.6% of physicians strongly or somewhat agreed with the question, “How familiar are you with pharmacogenomics?” even though nearly 20% of the physicians surveyed indicated that they had ordered a pharmacogenomic test within the past year. Of those respondents that had not ordered a pharmacogenomic test the most commonly cited reason was “Don't know which test to order” (69.7%). Almost half of all physicians anticipated ordering a pharmacogenomic test within the following year. Based on the results of the survey the authors conclude that physicians’ lack of understanding of pharmacogenomics remains a significant barrier to widespread implementation of pharmacogenomic testing. Thus, those of us in the PGx domain must do a better job of disseminating PGx information and educating physicians on the use of PGx knowledge. 

Read the full study and survey below:

Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties

Pharmacogenomics and personalized medicine (2014).

Dickinson Barry, D and Johansen Taber Katherine A. 

PGx analysis of 482 whole genomes

Few studies have analyzed whole genomes for PGx-related variants - instead, many utilize genotyping platforms made up of known variants. A recent analysis of 482 whole genome sequences has revealed interesting findings for 231 ADMET*-related genes:

• On average, each individual had a total of 17,733 variants in these genes.
• 4% of these were not annotated in dbSNP and potentially have functional significance.
• The percentage of novel variants identified was higher in ethnic populations under-represented by a DMET* genotyping platform coverage.

Focusing on CYP2C9, CYP2D6, VKORC1, UGT1A1 and TPMT pharmacogenes:

• 2521 novel variants were found within these genes. 
• 202 of these were in exons or proximal regulatory regions, and included novel missense, nonsense and frameshift variants.

Applying the analysis to a real-life clinical case, whole genomes of 7 Greek family members spanning 3 generations were annotated. Comparisons between two unrelated members of the family, who both undergo acenocoumarol treatment for atrial fibrillation (one of whom has responded well to treatment, the other has not), reveal clinical insights for these patients:

• 1/3 variants in ADMET*-related genes are different between the two patients, and include novel putatively functional variants. 
• The acenocoumarol non-responder is heterozygous for two variants in CYP2C9 (involved in acenocoumarol metabolism), whereas no CYP2C9 variants are found in the responder. 
• The acenocoumarol non-responder has no sequence variants in genes involved in the pathways of other anti-coagulation therapies (such as clopidogrel), and so this patient could consider switching medication as this may be more efficacious compared to acenocoumarol. 
• The acenocoumarol responder has known and novel variants within genes involved in the pathways of other anti-coagulation therapies and therefore should not modify their anticoagulation treatment, due to risk of adverse reactions or lack of efficacy.

Read the publication:
Personalized pharmacogenomics profiling using whole-genome sequencing.
Mizzi C, Peters B, Mitropoulou C, Mitropoulos K, Katsila T, Agarwal MR, van Schaik RH, Drmanac R, Borg J, Patrinos GP. Pharmacogenomics. 2014 Jun;15(9):1223-34. doi: 10.2217/pgs.14.102.


*ADMET = absorption, distribution, metabolism, excretion, toxicity.
    DMET = distribution, metabolism, excretion, toxicity. 

New PharmGKB pathway: Paroxetine

The paroxetine PK pathway is the newest addition to PharmGKB's pathway summaries.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of multiple psychiatric disorders including mood, panic, anxiety, and obsessive compulsive disorders. The pathway diagram depicts candidate genes mediating the transformation of paroxetine into its metabolites. The main enzyme responsible for the metabolism is cytochrome P450 2D6 (CYP2D6).

View the Paroxetine Pathway at PharmGKB for a summary of genetic variations in pharmacokinetic and pharmacodynamic genes that might affect paroxetine's metabolism and response. 

View all pathways at PharmGKB.

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.

European approval of additional CFTR variants listed for ivacaftor use

The drug Ivacaftor (Kalydeco) was originally indicated for use in cystic fibrosis (CF) patients with one or two copies of the G551D variant (rs75527207) in the CFTR gene. The European Commission has approved the use of ivacaftor in patients with an expanded list of CFTR variants that all result in a defect in CFTR gating (announced in a press release by the company).

The additional variants are: G178R (rs80282562), S549N (rs121908755), S549R (rs121908757 and rs121909005), G551S (rs121909013), G1244E (rs267606723), S1251N (rs74503330), S1255P (rs121909041) and G1349D (rs193922525). 

These additional variants were approved by the FDA earlier this year, and added to the ivacaftor drug label indication section. In light of these changes, the CPIC therapeutic guidelines for ivacaftor were updated. 

The variants are listed in Table 2 of the PharmGKB CFTR VIP summary - view to read more about targeting CFTR variants to treat CF.