Haplotypes of Aldosterone Synthase (Cyp11b2) Gene in the General Population of Japan: The Ohasama Study

Abstract

Since the identification of a chimeric aldosterone synthase which induces mendelian hypertension, polymorphisms in aldosterone synthase (CYP11B2) has been one of major targets for molecular analyses in association with hypertension. To date, four polymorphic variants of CYP11B2, -344T/C at promoter region, a gene conversion in intron 2, 2713A/G (in exon 3) which converts from Lys to Arg at codon 173 (K173R), and 4986T/C (in exon7) which converts from Val to Ala at codon 386 (V386A), have been identified in Caucasian population. Then, linkage disequilibrium between -344T/C polymorphism and a gene conversion in intron 2 or K173R mutation has been described, suggesting the presence of genetic haplotypes in Caucasians. Since the presence of a gene conversion in intron 2 or V386A mutation was still unknown in the Japanese population, all these polymorphisms were examined together to determine the CYP11B2 haplotypes of Japanese, using DNA samples from 1290 participants of the Ohasama study, who represent the general population of a rural community of northern Japan. Molecular analyses demon- strated the presence of a gene conversion of intron 2, but the absence of V386A mutation in Japanese population. The complete linkage disequilibrium between -344T/C polymorphism and K173R mutation was noted. Although -344T allele was linked either with a gene conversion in intron 2 or with normal intron 2, -344C allele was completely linked with normal intron 2. These results indicate the presence of 3 allelic haplotypes of CYP11B2, -344C with normal intron 2 and 173R, -344T with normal intron 2 and 173K, and -344T with converted intron 2 and 173K, in the general Japanese population. The frequency (total 1.0) was 0.35, 0.53, and 0.12, respectively. The presence of allelic haplotypes is considered to be an additional genetic information to individual polymorphism of CYP11B2 to determine the linkage between CYP11B2 polymorphisms and hypertension.

CYP11B2 Polymorphisms and Home Blood Pressure in a Population-Based Cohort in Japanese: the Ohasama Study

“…We previously reported an absolute linkage disequilibrium between the 344C/T and R173K polymorphisms, and a close linkage between 344T and the intron 2 sequence conversion in the general Japanese population, forming the three allelic haplotypes (13). In this study we failed to find the V386A mutation of CYP11B2 (13), which has been reported in Caucasians (4).…”

“…Three genetic polymorphisms of CYP11B2, 344C/T at the promoter region, a conversion in intron 2 from the CYP11B2 sequence to that of CYP11B1, and R173K in exon 3, were examined as reported previously (13). Briefly, 344C/T and R173K polymorphisms were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and the presence or absence of intron 2 conversion was determined by allele-specific PCR (13).…”

“…Briefly, 344C/T and R173K polymorphisms were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and the presence or absence of intron 2 conversion was determined by allele-specific PCR (13).…”

The impact of the clinical CYP11B2 mutation V386A strongly depends on the enzyme’s genetic background

“…In this study, we aimed at a comparision between human CYP11B2 carrying a lysine or a arginine, repectively at postion 173, which is a common polymorphism in the CYP11B2 gene [10], in combination with the mutation V386A. Therefore, investigations in a reconsituted in vitro system containing purified CYP11B2, Adx and AdR in HEPES, pH 7.4, were performed.…”

“…One of them carries either a lysine or an arginine at position 173 of the amino acid chain. A haplotype study in Japan (547 examined persons) revealed a frequency of 46% for the lysine variant, 45% were heterozygous for lysine and arginine and 9% carried an arginine residue at this position [10]. A comparison of the two CYP11B2 variants was performed by Zhang et al utilizing a cell culture system [12].…”