Genetic signature consistent with selection against the CYP3A4 1B allele in non-African populations

Abstract

Cytochrome P450 3A enzymes (CYP3A) play a major role in the metabolism of steroid hormones, drugs and other chemicals, including many carcinogens. The individually variable CYP3A expression, which remains mostly unexplained, has been suggested to affect clinical phenotypes. We investigated the CYP3A locus in five ethnic groups. The degree of linkage disequilibrium (LD) differed among ethnic groups, but the most common alleles of the conserved LD regions were remarkably similar. Non-African haplotypes are few; for example, only four haplotypes account for 80% of common European Caucasian alleles. Large LD blocks of high frequencies were suggestive of selection. Accordingly, European Caucasian and Asian cohorts each contained a block of single nucleotide polymorphism (SN Ps) with very high P excess values. The overlap between these blocks in these two groups contained only two of the investigated 26 SNPs and one of them was the CYP3A4 1B allele. The region centromeric of CYP3A4 lB exhibited high haplotype homozygosity in European Caucasians as opposed to Africa n-Americans. CYP3A4 lB showed a moderate effect on CYP3A4 mRNA and protein expression, as well as on CYP3A activity assessed as (V)max of testosterone 6 beta-hydroxylation in a liver bank. Our data are consistent with a functional relevance of CYP3A4 1B and with selection against this allele in non-African populations. The elimination of CYP3A4 1B involved different parts of the CYP3A locus in European Caucasians and Asians. Because CYP3A4 is involved in the vitamin D metabolism, rickets may have been the underlying selecting factor. Pharmacogenetics and Genomics 16:59-71. (c) 2006 Lippincott Williams & Wilkins.