Mining local exome and HLA data to characterize actionable pharmacogenetic variants in Saudi Arabia

Abstract Pharmacogenomics (PGX) is a promising field of precision medicine where efficacy of drugs is maximized while side effects are minimized for individual patients. Knowledge of the frequency of PGX-relevant variants in the local population is a pre-requisite to informed policy making. Unfortunately, such knowledge is largely lacking from the Middle East. Here, we describe the use of a large clinical exome database (n=13,473) and HLA haplotypes (n=64,737) from Saudi Arabia, one of the largest countries in the Middle East, to ascertain allele frequencies of known PGX variants. In addition, we queried another exome database (n=816) of well-phenotyped research subjects from Saudi Arabia to discover novel PGX candidate variants. Although our results show that only 26% (63/242) of class 1A/1B PharmGKB variants were identified, we estimate that 99.57% of the local population have at least one PGX variant (class 1A/1B PharmGKB). This translates to a minimum estimated impact of 9% of medications dispensed by our medical center annually. We also highlight the contribution of rare variants where 71% of the genes devoid of common PGX variants had at least one potentially deleterious rare variant. Thus, we show that approaches that go beyond the use of commercial PGX kits that have been optimized for other populations should be implemented to ensure universal and equitable access of all members of the local population to personalized prescription practices.