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

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.

Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles

“…In conclusion, our interrogation of CMA data from almost 100,000 individuals identified low frequency pharmacogenomic CNVs at the clinically relevant CYP2C region in the general population. These results are consistent with previously reported pharmacogenomic sequencing studies, which identified a spectrum of rare pharmacogenomic variants that are likely to be functional (Bush et al, ; Gordon et al, ; Li et al, ; Nelson et al, ). Although the identified CYP2C deletion and duplication alleles have low frequencies in the studied populations, their contribution to an individual's CYP2C19 and CYP2C9 metabolizer phenotype status is most likely clinically relevant.…”

“…In conclusion, our interrogation of CMA data from almost 100,000 individuals identified low frequency pharmacogenomic CNVs at the clinically relevant CYP2C region in the general population. These results are consistent with previously reported pharmacogenomic sequencing studies, which identified a spectrum of rare pharmacogenomic variants that are likely to be functional (Bush et al, 2016;Gordon et al, 2014;Li et al, 2014;Nelson et al, 2012…”

“…Recent studies that utilized large high‐throughput sequencing datasets for pharmacogenomic variant discovery prompted our interrogation of deidentified CMA data from 99,695 individuals for pharmacogenomic CNV discovery at the clinically relevant CYP2C gene cluster region. Consistent with the sequencing studies that identified novel coding variants in pharmacogenomic genes (Bush et al, ; Gordon et al, ; Li et al, ; Nelson et al, ), our large CNV study resulted in the discovery of pharmacogenomic deletion and duplication alleles at the CYP2C region. The full gene and partial‐gene CYP2C19 deletions have been designated by the PharmVar Consortium as CYP2C19 *36 and CYP2C19 *37, respectively (http://www.pharmvar.org).…”

“…( (Bush et al, 2016;Gordon et al, 2014;Li et al, 2014;Nelson et al, 2012), our large CNV study resulted in the discovery of pharmacogenomic deletion and duplication alleles at the CYP2C region. The full gene and partial-gene CYP2C19 deletions have been designated by the PharmVar Consortium as CYP2C19*36 and CYP2C19*37, respectively (www.pharmvar.org).…”

Symptom Experience, Management, and Outcomes According to Race and Social Determinants Including Genomics, Epigenomics, and Metabolomics (SEMOARS + GEM): an Explanatory Model for Breast Cancer Treatment Disparity

“…ADME-related genetic variability often differs across populations [94] and helps to explain the link between ancestry and variable chemotherapy drug response [95]. Li et al observed greater diversity in ADME genes for the African-American population compared with European and African populations [96], predisposing African-Americans to more variable drug response. Gene variations may alter drug metabolism by activating or inactivating a medication, activating or inactivating a drug's metabolite, affecting the medication's transport, or affecting the drug's intended target [97].…”