Increased genetic diversity of ADME genes in African Americans compared with their putative ancestral source populations and implications for pharmacogenomics.

Jing Li,Dongsheng Lu,Lei Tian,Shuhua Xu,Chao Zhang,Xingzhen Lao

doi:10.1186/1471-2156-15-52

Abstract

BackgroundAfrican Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies. However, the contribution of European ancestry is expected to result in considerable differences in the genetic architecture of African American individuals compared with an African genome. In particular, the genetic admixture influences the genomic diversity of drug metabolism-related genes, and may cause high heterogeneity of drug responses in admixed populations such as African Americans.ResultsThe genomic ancestry information of African-American (ASW) samples was obtained from data of the 1000 Genomes Project, and local ancestral components were also extracted for 32 core genes and 252 extended genes, which are associated with drug absorption, distribution, metabolism, and excretion (ADME) genes. As expected, the global genetic diversity pattern in ASW was determined by the contributions of its putative ancestral source populations, and the whole profiles of ADME genes in ASW are much closer to those in YRI than in CEU. However, we observed much higher diversity in some functionally important ADME genes in ASW than either CEU or YRI, which could be a result of either genetic drift or natural selection, and we identified some signatures of the latter. We analyzed the clinically relevant polymorphic alleles and haplotypes, and found that 28 functional mutations (including 3 missense, 3 splice, and 22 regulator sites) exhibited significantly higher differentiation between the three populations.ConclusionsAnalysis of the genetic diversity of ADME genes showed differentiation between admixed population and its ancestral source populations. In particular, the different genetic diversity between ASW and YRI indicated that the ethnic differences in pharmacogenomic studies are broadly existed despite that African ancestry is dominant in Africans Americans. This study should advance our understanding of the genetic basis of the drug response heterogeneity between populations, especially in the case of population admixture, and have significant implications for evaluating potential inter-population heterogeneity in drug treatment effects.

Highlights

African Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies
Ancestral origins of ADME genes in African Americans Estimating the local admixture proportions of genes could help to understand the genetic differences between admixed and ancestral source populations, and to investigate the natural selection that has occurred since admixture [16]
An ASW individual (NA19625), who is presented as first two rows in each box, exhibited two haplotypes of the ABCB1 gene that originated from Europeans (Figure 1A), two haplotypes of the CYP3A4 gene that originated from Africans (Figure 1B), and haplotypes of the CYP1A2 gene that originated from Europeans and Africans separately (Figure 1C)

Summary

Introduction

African Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies. The genetic admixture influences the genomic diversity of drug metabolism-related genes, and may cause high heterogeneity of drug responses in admixed populations such as African Americans. Many factors such as age, enzyme induction or inhibition, and diseases can affect enzyme activity. Previous studies highlighted the contributions of both environmental and, in particular, genetic factors to variations in the activity of ADME proteins [4,5]. The careful assessment of the contributions of ADME genetic variations to the efficacy and safety of drugs is an important task for the development of clinical pharmacogenetic studies

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