Abstract
The products of the polymorphic ADME genes are involved in Absorption, Distribution, Metabolism, and Excretion of drugs. The pharmacogenetic data have been studied extensively due to their clinical importance in the appropriate drug prescription, but such data from the isolated populations are rather scarce. We analyzed the distribution of 95 polymorphisms in 31 core ADME genes in 20 populations worldwide and in newly genotyped samples from the Roma (Gypsy) population living in Croatia. Global distribution of ADME core gene loci differentiated three major clusters; (1) African, (2) East Asian, and (3) joint European, South Asian and South American cluster. The SLCO1B3 (rs4149117) and CYP3A4 (rs2242480) genes differentiated at the highest level the African group of populations, while NAT2 gene loci (rs1208, rs1801280, and rs1799929) and VKORC1 (rs9923231) differentiated East Asian populations. The VKORC1 rs9923231 was among the investigated loci the one with the largest global minor allele frequency (MAF) range; its MAF ranged from 0.027 in Nigeria to 0.924 in Han Chinese. The distribution of the investigated gene loci positions Roma population within the joined European and South Asian clusters, suggesting that their ADME gene pool is a combination of ancestral (Indian) and more recent (European) surrounding, as it was already implied by other genetic markers. However, when compared to the populations worldwide, the Croatian Roma have extreme MAF values in 10 out of the 95 investigated ADME core gene loci. Among loci which have extraordinary MAFs in Roma population two have strong proof of clinical importance: rs1799853 (CYP2C9) for warfarin dosage, and rs12248560 (CYP2C19) for clopidogrel dosage, efficacy and toxicity. This finding confirms the importance of taking the Roma as well as the other isolated populations`genetic profiles into account in pharmaco-therapeutic practice.
Highlights
Medication efficacy and adverse drug reactions are associated with specific genes’ variants [1] that are related to the Absorption, Distribution, Metabolism and Elimination of drugs (ADME)
The minor allele frequencies (MAFs) and sample sizes as well as the references in addition to the 1000 Genomes for all 95 single nucleotide polymorphisms (SNPs) used in the this study are presented in the S1 Table
MAF always refers to the global minor allele as indicated in 1000 Genomes’ database
Summary
Medication efficacy and adverse drug reactions are associated with specific genes’ variants [1] that are related to the Absorption, Distribution, Metabolism and Elimination of drugs (ADME). ADME genes variation in Roma and 20 populations worldwide together with a number of factors such as sex, age, weight, concomitant medication, health status, comorbidity level etc. Lacking large-scale pharmacogenomics information in this population presents a bottleneck for their healthcare improvement
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