Matsubara M, Omori F, Fujita S, Metoki H, Kikuya M, Fujiwara T, Araki T, Imai Y
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Medicine and Pharmaceutical Science, Sendai, Japan.
Clin Exp Hypertens. 2001 Nov;23(8):603-10. doi: 10.1081/ceh-100107390.
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.
自从发现一种可导致孟德尔型高血压的嵌合型醛固酮合酶以来，醛固酮合酶（CYP11B2）的多态性一直是与高血压相关的分子分析的主要靶点之一。迄今为止，在白种人群中已鉴定出CYP11B2的四种多态性变体，即启动子区域的-344T/C、内含子2中的基因转换、2713A/G（外显子3中），该转换导致密码子173处的赖氨酸转换为精氨酸（K173R），以及4986T/C（外显子7中），该转换导致密码子386处的缬氨酸转换为丙氨酸（V386A）。随后，有人描述了-344T/C多态性与内含子2中的基因转换或K173R突变之间的连锁不平衡，这表明白种人中存在基因单倍型。由于在日本人群中内含子2中的基因转换或V386A突变的存在情况仍不清楚，因此使用来自Ohsama研究的1290名参与者的DNA样本，对所有这些多态性进行了联合检测，以确定日本人的CYP11B2单倍型，这些参与者代表了日本北部一个农村社区的普通人群。分子分析表明，日本人群中存在内含子2的基因转换，但不存在V386A突变。注意到-344T/C多态性与K173R突变之间存在完全连锁不平衡。虽然-344T等位基因与内含子2中的基因转换或正常内含子2相关联，但-344C等位基因与正常内含子2完全相关联。这些结果表明，在日本普通人群中存在CYP11B2的3种等位基因单倍型，即-344C与正常内含子2和173R、-344T与正常内含子2和173K，以及-344T与转换后的内含子2和173K。其频率（总计为1.0）分别为0.35、0.53和0.12。等位基因单倍型的存在被认为是CYP11B2个体多态性的额外遗传信息，有助于确定CYP11B2多态性与高血压之间的联系。
