Friday, August 22, 2014

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. 

Tuesday, August 19, 2014

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.

Wednesday, August 6, 2014

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.

Monday, August 4, 2014

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.

Tuesday, July 29, 2014

Praise for PharmGKB

PharmGKB is “the Holy Grail” for DNA STAT, a company that provides pharmacogenomics testing for patients. DNA STAT goes on to praise PharmGKB’s “accessibility and comprehensiveness” and highlights its “interactive SNP features and tools for education and clinical implementation of genetic data.”

Friday, July 25, 2014

Ifosfamide PK and PD pathways published in PG&G

Ifosfamide is a produg used in combination chemotherapy for the treatment of solid tumors. Around 20% of patients experience toxicity. Pathways depicting the genes involved in the pharmacokinetics and pharmacodynamics of ifosfamide have been published in PG&G. Variants in these genes that are associated with toxicity and drug resistance are discussed.

Click on the pictures to view the pathways:

Read the publication:
PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics.
Lowenberg D, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE.
Pharmacogenetics & Genomics. 2014 Feb;24(2):133-8.

Wednesday, July 16, 2014

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.