A population study of clinically actionable genetic variation affecting drug response from the Middle East

Abstract

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Fig. 1. Comparison of actionable genotype or diplotype frequencies in the Qatari population.

Actionable frequencies are compared between the Qatari cohort (n = 6045) and (a) the overall 1000 genomes cohort (n = 2504), or (b) the European superpopulation in the 1000 genomes cohort (n = 503). p values of significantly differing frequencies with Bonferroni adjustment indicated as follows: *= 0.0001 ≤ p value < 0.05, **= 0.000001 < p value < 0.0001, ***= p value ≤ 0.000001.

Fig. 2. Actionable genotype or diplotype frequencies in the Qatari subpopulations.

(a) Actionable genotype/diplotype frequencies of clinically important pharmacogenes in the Qatari population and subpopulations (shown as orange bars) along with that of the overall 1000 genomes and the superpopulations (shown as blue bars). (b) Clustering of QGP subpopulations based on F_ST calculated from the pharmacogenes. (c) Comparison of the actionable frequencies of QGP General Arab and Peninsular Arab subgroups. QGP subpopulations PAR, Peninsular Arabs; GAR, General Arabs; ADM, Admixed; WEP, West Eurasian/Persian; AFR: African; SAS, South Asian; 1KG, thousand genomes superpopulations: EUR, European; AMR, American; AFR: African; SAS, South Asian; EAS, East Asian.

Fig. 3. Warfarin dosing prediction.

Distribution of the predicted weekly dose (mg) of warfarin in the Qatari population (yellow) using the IWPC algorithm based on age, sex, height, weight, ethnicity, the concurrent use of drugs that decrease warfarin requirements, and the genotypes/diplotypes of VKORC1 and CYP2C9. Also shown is the distribution of dosage in patients of European ethnicity from the EU-PACT trial (blue). Weekly doses in mg are plotted in the Y-axis for the two populations. The box is drawn with the interquartile range and the central horizontal line showing the median, while values above the range shown as whiskers. Individuals with values ≤21 mg per week (below the bottom horizontal line) would be predicted to need a lower dose, and those with values ≥49 mg per week (above the top horizontal line) would be predicted to need a higher dose.