Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations

Abstract

Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in "pharmacogenes". The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.

Figure 1

Distribution of variants according to MAF. MAF minor allele frequency.

Figure 2

Distribution of the detected variants according to their functional predictions. SNV single nucleotide variant.

Figure 3

Heatmap for comparison of MAF in UAE to 10 other populations. Top right: color scale according to allele frequency, Red rs-numbers designate variants that have level 1 and 2 PhramGKB annotations, while the black rs-numbers designates variants with level-3 PhramGKB annotations. Afr African, Eas_As East Asians, GME-all Greater Middle East whole sample, UAE frequencies in the current study, Sou_As South Asia, Eur_Fin European Finnish, GnomAD_All frequencies from GnomAD whole samples.