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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.
Highlights
Genetic variation plays an important role in the inter-individual differences in response to medications, and pharmacogenomic (PGx) testing has the potential to provide an informed decision on the appropriate choice and dosage of medications[1]
We performed a comprehensive analysis of the variants annotated by PharmGKB to be associated with drugs and based on adjusted p-values from two proportions z-test, the allele frequencies of 1320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population (6,045 whole genomes) and other world populations represented in the gnomAD v3 dataset (76,156 whole genomes) (Supplementary Data S15)
These differing allele frequencies in the Qatari population compared to other populations provides an avenue for further work in the future to determine whether the clinical outcomes are different based on reported drug-gene associations in other ethnic groups[17,18,19]
Summary
Genetic variation plays an important role in the inter-individual differences in response to medications, and pharmacogenomic (PGx) testing has the potential to provide an informed decision on the appropriate choice and dosage of medications[1]. The current progress in next-generation sequencing (NGS) technologies provides several avenues for PGx profiling. Many studies have promoted exome sequencing or targeted NGS panels for PGx testing at population scale[2,3], the benefits of these approaches are mostly limited by their inability to sequence the non-coding regions[4]. Whole-genome sequencing (WGS) can overcome this limitation and provide the most comprehensive sequencing approach for more accurate PGx profiling[5]. WGS provides more accurate PGx profiling through the ability to identify potential rare variants/private mutations that may affect drug disposition and response. Resources such as the PharmVar[6,7] and Pharmacogenomics
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