Genetic variations in drug-metabolizing enzyme CYP2C9 among major ethnic groups of Pakistani population

Abstract

The genetic polymorphism of cytochrome P450 (CYPs)drug-metabolizing enzymes are well studied in human populations for drug safety and efficacy. CYP2C9 is a highly polymorphic CYP enzyme that oxidizing the indigenous compounds and xenobiotics. The present study was pursued to evaluate the genetic variation across the CYP2C9 gene among major groups of the Pakistani population. The CYP2C9 genomic region holding important warfarin drug-metabolizing SNPs was sequenced from 159 individuals belong from five major ethnic groups of Pakistani population. The population genetic analyses of the high-quality sequences data was performed using Arlequin v3.5, DnaSP v6.12 and Network 5 resources. The data analyses unveiled that genetic variance among samples mainly arose from population-scale differentiation among these ethnic groups with global Fst of 0.78, P-value < 0.0001. The highest pairwise population genetic variation observed between Saraiki and Baloch groups based on different statistical tests. Whereas, uniform genetic composition across CYP2C9 loci was inferred among Punjabi, Pathan and Sindhi groups with minimal genetic differentiation. Several SNPs, including the previously reported warfarin associated variants, i.e. rs2860905, rs1799853 (CYP2C9*2) and rs72558189 (CYP2C9*14) were detected in these population groups with diverse allelic frequencies. Besides, a novel intronic SNP, i.e. not available in dbSNP and Ensemble databases, was identified for a Sindhi individual sample. This novel SNP predicted to influence the CYP2C9 alternative transcript splicing. The pharmacogeneticsassessment of the CYP2C9 genetic variations identified in current study may important to test against the warfarin efficacy for different ethnicity of Pakistani population.

Keywords: CYP2C9; Drug-metabolizing enzyme; Genetic variations; Pakistani population.