Analysis of CYP3A4 genetic polymorphisms in Han Chinese

Our study aimed to comprehensively investigate the genetic polymorphisms of CYP3A4 in Han Chinese. We sequenced the generegions of CYP3A4, including its promoter, exons, surrounding introns and 3¢ untranslated region (3¢UTR), from 100 unrelated-healthy Han Chinese individuals. We detected 11 SNPs, three of which are novel. According to in silico functional predictionof novel variants, 20148 A4G in exon 10, resulting in substitution of Tyr319 with Cys (CYP3A4*21), may induce dramaticalteration of protein conformation, and 26908 G4Ain3¢UTR may disrupt post-transcriptional regulation. We identified fivealleles in Han Chinese, the allele frequencies of CYP3A4*1, *5, *6, *18 and *21 are 97, 0.5, 1, 1 and 0.5%, respectively.Haplotype inference revealed 14 haplotypes, of which the major haplotype CYP3A4*1A constitutes 59% of the totalchromosomes. We also examined the possible role of natural selection in shaping the variation of CYP3A4 and confirmeda trend, consistent with the action of positive selection. We systematically screened the genetic polymorphisms of CYP3A4in Han Chinese, highlighted possible functional impairment of the novel allele and summarized the distinct allele and haplotypefrequency distribution, with an emphasis on detecting the footprint of recent positive selection on the CYP3A4 gene inHan Chinese.Journal of Human Genetics advance online publication, 17 March 2011; doi:10.1038/jhg.2011.30Keywords: CYP3A4; Han Chinese; genetic polymorphismsINTRODUCTIONCytochrome P450 3A4 (CYP3A4, MIM 124010), together withCYP3A5 (MIM 605325), CYP3A7 (MIM 605340) and CYP3A43(MIM 606534), are members of the CYP3A subfamily forming agene cluster on chromosome 7q22. CYP3A4, as the most abundantlyexpressed P450 isoenzyme in human liver, contributes to the oxidativemetabolism of approximately 50% of clinically-used drugs, with abroad range of substrate specificity. For instance, CYP3A4 is involvedin the oxidation of certain antibiotics, calcium channel blockers,antidepressants, immunosuppressants, HMG-CoA reductase inhibi-tors (HMGs), antihistamines and protease inhibitors, as well as someendogenous steroids, such as cortisol, testosterone and estradiol.The enzyme activity of CYP3A4 shows wide interindividual varia-bility (up to 60-fold),