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

BMC Genetics

Research Article

Shuhua Xu¹  Dongsheng Lu¹  Chao Zhang¹  Lei Tian¹  Jing Li¹  Xingzhen Lao² 

[1] Max Planck Independent Research Group on Population Genomics, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China;School of Life Science and Technology, China Pharmaceutical University, 210009, Nanjing, China;

关键词: ADME genes;    African Americans;    Drug response heterogeneity;    Genetic diversity;    Genetic admixture;   

DOI  :  10.1186/1471-2156-15-52

 received in 2013-10-24, accepted in 2014-04-24,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Li et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.