HAPLOTYPE STRUCTURE AND ALLELE FREQUENCIES OF CYP2B6 IN A KOREAN POPULATION

Abstract

ABSTRACT:Cytochrome P450 2B6 (CYP2B6) metabolizes a number of therapeutic drugs and its metabolic activity varies markedly in human liver. Although genetic polymorphisms of CYP2B6 have been reported in noncoding and coding regions, little information is available regarding single nucleotide polymorphisms (SNPs) and their haplotypes in noncoding regions in Asians. Fourteen previously reported SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism or SNaPshot analysis in a Korean population and their haplotypes were inferred from genotype data using an expectation-maximization algorithm. The most common haplotypes were haplotype I, the reference sequence (frequency 0.35), haplotype II (0.19), haplotype III (0.19), and haplotype V (0.12), which together accounted for 85% of all haplotypes. The frequency of haplotype III, which contains ؊2320C, ؊1778G, ؊1186G, ؊750C, and 15582T, was found to be 2.4-fold higher than that of the *1J allele in Caucasians, and the frequency of haplotype V, which contains ؊8207C, ؊1456C, ؊750C, 516T, and 785G, was 55% of that of the *6B allele in Caucasians. Moreover, haplotype V, the *6B allele, appeared to be completely linked to ؊8207 within a putative nuclear receptor binding motif, suggesting that lower expressions of the *6B allele may be associated with the presence of noncoding SNPs such as ؊8207G>C linked to nonsynonymous SNPs. In conclusion, we found 11 previously described polymorphisms and identified four major haplotypes of CYP2B6 in Koreans. The frequencies of the *1J or *6B alleles, which may reduce CYP2B6 enzyme expression, were found to be significantly different between Koreans and Caucasians.

Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index

“…Consistent with a previous report on the Korean population [7], the frequencies of the CYP2B6*9, *4, and *6 alleles in the 374 Korean subjects were 0.4%, 7.0% and 16.2%, respectively. The allelic frequencies were in HardyWeinberg equilibrium (c 2 = 5.16, P = 0.27).…”

“…In particular, the CYP2B6*6 allele is defined by two non-synonymous single nucleotide polymorphisms, 516G>T (Q172H) and 785A>G (K262R). This allele is clinically important because its frequency differs greatly in different populations (from 12% in Koreans [7] to 62% in Papua New Guineans [8]) and because it is associated with significantly decreased in vitro metabolism of EFV and an increase in adverse effects of EFV in HIV patients [9,10].…”

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

“…In this study, TT genotype patients accounted for 28% of the total (7 of 25 patients), which is similar to that reported by Kwara et al, who observed that 27% of West African patients (7 of 26) had the TT genotype (18). We obtained a T allele frequency of 0.44, which is higher than that reported in Koreans (0.14), Japanese (0.16), Caucasians (0.25), white Americans (0.25), and African Americans (0.28) but similar to that of West Africans (0.42), Chinese (0.43), and Hispanics (0.43) (8,16,37). However, the number of patients genotyped for CYP2B6 G516T polymorphism was quite small.…”

Identification and Analysis of Conserved Sequence Motifs in Cytochrome P450 Family 2

“…Data from numerous site-directed mutagenesis, directed evolution, and genetic polymorphism studies strongly suggest the role of non-active site regions/residues in P450 expression, stability, ligand binding, and/or catalytic activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). X-ray crystallography, solution thermodynamics, and site-directed and random mutagenesis have provided some clues about the role of these regions/residues in enzyme functions.…”