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.