Published Online
on July 24, 2006

A more recent version of this article appeared on September 1, 2006

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Submitted on December 11, 2005
Revised on January 4, 2006

Mutation of the Follicle-Stimulating Hormone Receptor Gene 5'-Untranslated Region Associated With Female Hypertension

Tomohiro Nakayama^*; Nobuhiro Kuroi; Morihiko Sano; Yasuharu Tabara; Tomohiro Katsuya; Toshio Ogihara; Yoshio Makita; Akira Hata; Michiko Yamada; Norio Takahashi; Nobuhito Hirawa; Satoshi Umemura; Tetsuro Miki; and Masayoshi Soma

From the Division of Molecular Diagnostics (T.N.), Advanced Medical Research Center, and Division of Nephrology and Endocrinology (M.S.), Department of Medicine, Nihon University School of Medicine (N.K., M.S.), Tokyo, Japan; Departments of Basic Medical Research and Education (Y.T.) and Geriatric Medicine (T.M.), Ehime University Graduate School of Medicine, Ehime, Japan; Department of Geriatric Medicine (T.K., T.O.), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Pediatrics (Y.M.), Asahikawa Medical College, Asahikawa, Japan; Department of Public Health (A.H.), Graduate School of Medicine, Chiba University, Chiba, Japan; Departments of Clinical Studies (M.Y.) and Genetics (N.T.), Radiation Effects Research Foundation; and the Department of Medical Science and Cardiorenal Medicine (N.H., S.U.), Yokohama City University Graduate School of Medicine, Yokohama City, Japan.

^* To whom correspondence should be addressed. E-mail: tnakayam{at}med.nihon-u.ac.jp.

Abstract--Inactivating mutations in the follicle-stimulating hormone receptor (FSHR) gene have been reported to cause hereditary hypergonadotropic ovarian failure. It has been found recently that the FSHR knockout mouse exhibits hypertension. The aim of the present study was to investigate the association between polymorphisms in the human FSHR gene and essential hypertension (EH) by using single nucleotide polymorphisms (SNPs). We selected 5 SNPs in the gene (rs1394205, rs2055571, rs11692782, rs1007541, and rs2268361) and performed 2 genetic case-control studies in different populations. A confirmative case-control study was performed using 1035 EH patients and 1058 age-matched controls. Transcriptional activities were measured with a luciferase assay system. The first case-control study found that the A allele of rs1394205 was significantly higher in EH females (P=0.010). In addition, in the confirmative case-control study, there was a significant difference for this SNP between female normotensive subjects (44.5%) and EH patients (50.7%) (P=0.043). Multiple logistic regression analysis in female subjects also revealed a significant association of subjects with the A allele of rs1394205 with EH (P=0.033), with the odds ratio calculated as 1.68 (95% CI: 1.04 to 2.73). Transcriptional activity of the A allele was 56±8% (mean±SD) of that observed for the G-type allele (P=0.001). Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004). The SNP in the 5'-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women.

Key words: hypertension, essential • hormones • case-control studies

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