Published online before print July 24, 2006, doi: 10.1161/01.HYP.0000233877.84343.d7
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(Hypertension. 2006;48:512.)
© 2006 American Heart Association, Inc.
Original Articles |
Mutation of the Follicle-Stimulating Hormone Receptor Gene 5'-Untranslated Region Associated With Female Hypertension
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.
Correspondence to Tomohiro Nakayama, Division of Molecular Diagnostics, Advanced Medical Research Center, Nihon University School of Medicine, Ooyaguchi-kamimachi, 30-1 Itabashi-ku, Tokyo 173-8610, Japan. E-mail tnakayam{at}med.nihon-u.ac.jp
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Abstract |
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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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Introduction |
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It is likely that essential hypertension (EH) is a polygenic disorder that results from the inheritance of a number of susceptibility genes. The causal genes identified may contribute from 30% to 50% of the variations in blood pressure seen among individuals.1 These genetic determinants interact with environmental factors, such as dietary salt, to produce the final disease phenotype. Despite significant recent progress in genomic and statistical tools, the genetic dissection of human EH remains a major challenge.2
The effects of follicle-stimulating hormone (FSH) are mediated by its interaction with specific receptors and the activation of Gs, the stimulatory guanine nucleotide binding protein, which stimulates the enzyme adenylyl cyclase.3 The FSH receptor (FSHR) belongs to the superfamily of G protein–coupled receptors that are characterized by the common structural feature of 7 transmembrane domains. They differ structurally from other G protein–coupled receptors in that they contain a large extracellular domain in the amino-terminal part of the receptor protein, which is required for interaction with complex glycoprotein hormones.4–6 The human FSHR gene is localized to 2p21 to p16 and is composed of 10 exons.7 The 5'-flanking region of the gene has neither a TATA nor a CCAAT box and exhibits promoter-type features that are seen in housekeeping genes.8
Inactivating mutations in the FSHR gene have been reported to cause hereditary hypergonadotropic ovarian failure in women.9 These mutations have been shown to be associated with a recessive inheritance pattern, and all of the affected subjects have homozygous or compound heterozygous mutations in the coding region of the gene. The phenotype in men for this particular FSHR mutation is less clear, with homozygous men found to have normal masculinization and circulating testosterone, normal or slightly elevated luteinizing hormone (LH), moderately elevated FSH, and slightly to severely reduced testicular volume.10 Although men with inactivating mutations have abnormal semen parameters that range from severe-to-moderate oligozoospermia, normal sperm concentrations with low volumes, or teratozoospermia (reported in 1 individual), none have been found to be azoospermic, and there are reports of such individuals fathering children. These results suggest that FSHR mutations have a greater consequence in women than in men.
The FSHR knockout mice have ovarian insufficiency, low estrogen levels with functionally responsive estrogen receptors, and increased testosterone levels.11–13 They also exhibit the same changes seen in postmenopausal women, such as osteoporosis, hypercholesterolemia, and weight gains. In 2003, Javeshghani et al14 reported that these mice have increased blood pressure, indicating that there is vascular remodeling.
There have been no previous studies on the association between the FSHR gene and EH. The aim of the present study was to investigate the association between the human FSHR gene and EH through the use of single nucleotide polymorphisms (SNPs) in the human FSHR gene.
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Methods |
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First Case–Control Study
Patients and control subjects from the northern area of Tokyo were recruited for the first case–control screening study. A total of 235 patients were diagnosed with EH according to the following criteria: seated systolic blood pressure (SBP) >160 mm Hg and/or diastolic blood pressure (DBP) >100 mm Hg on 3 occasions within 2 months after the first medical examination. None of the patients were using antihypertensive medications, and subjects diagnosed with secondary hypertension were excluded. We also included 237 normotensive (NT) healthy individuals as controls. None of the NT participants had a family history of hypertension, and all had SBP and DBP <130 and 85 mm Hg, respectively. A family history of hypertension was defined as a previous diagnosis of hypertension in grandparents, uncles, aunts, parents, or siblings. Informed consent was obtained from each individual as per a protocol approved by the Human Studies Committee of Nihon University.15
Confirmative Case-Control Study: Subgroup Collaboration Study With the Hypertensive Section of the Japanese Millennium Project
For confirmation of a possible SNP association, we used a second set of 1035 EH patients and 1058 age-matched control subjects, who were recruited through a subgroup collaboration study with the hypertensive section of the Japanese Millennium Project. Six medical institutes took part in the collaborative study and collected data on hypertensive cases and controls. Hypertensive patients were defined as having SBP 
140 mm Hg or DBP 90 mm Hg or were patients with chronic antihypertensive medication. To increase the statistical power of the present study, hypertensive subjects additionally had to meet the following criteria: age <60 years old or onset of hypertension <50 years of age, a family history of hypertension, and without obesity (body mass index <26 kg/m2). The NT criteria were as follows: SBP/DBP <130/85 mm Hg, without a family history of hypertension, and without obesity. In this study, both groups were recruited from throughout Japan, and informed consent was obtained from each individual as per the protocol approved by each institutions’ human studies committee.
Biochemical Analysis
Serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol, uric acid, creatinine, and 
-glutamyl transpeptidase were measured using the methods of the clinical laboratory department of each hospital or institution.
Genotyping
Using information about allelic frequencies of SNPs registered on the web site of the National Center for Biotechnology Information and Celera Discovery System-Applied Biosystems, 5 SNPs with minor allele frequencies >20% were selected. SNPs with relatively high minor allele frequencies have been shown to be very useful as genetic markers for genetic case–control studies.
We examined the association between EH and 5 SNPs in the human FSH receptor gene. All 5 of the SNPs were confirmed using the National Center for Biotechnology Information web site and Applied Biosystems-Celera Discovery System with the accession numbers, rs1394205 (C_426553_10), rs2055571 (C_246842_10), rs11692782 (C_228130_10), rs1007541 (C_9561251_1_), and rs2268361 (C_11813031_1_; Figure 1 a). Genotypes were determined using Assays-on-Demand kits (Applied Biosystems) together with TaqMan PCR.16 When allele-specific fluorogenic probes hybridize to the template during the PCR, the 5' nuclease activity of Taq polymerase can discriminate alleles. Cleavage results in increased emission of a reporter dye that otherwise is quenched by the dye minor groove binder (MGB). Each 5' nuclease assay requires 2 unlabeled PCR primers and 2 allele-specific probes. Each probe is labeled with a reporter dye (VIC [a proprietory dye from Applied Biosystems] and 6-carboxyfluorescein [FAM]) at the 5' end and MGB at the 3' end. Amplification by PCR preceded using TaqMan Universal Master Mix (PE Biosystems) in a 25-µl reaction volume containing 50 ng of DNA, 700 nM primer, and 100 nM probe final concentrations. Thermal cycling conditions consisted of 95°C for 10 minutes and then 40 cycles of 92°C for 15 s and 60°C for 1 minute in a GeneAmp 9700 system. Fluorescence levels of the PCR products were measured using an ABI PRISM 7700 Sequence Detector (Applied Biosystems), which resulted in 3 genotypes of 2 alleles being clearly identified. We analyzed cis elements in the 5' upstream region of the gene using AliBaba2 software that was obtained from the Biological Databases web site (http://www.gene-regulation.com/pub/programs.html#alibaba2).
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, exons, and —, indicate introns. b, Pairwise LD in the FSH receptor gene, as evaluated by D' and r2. Pairwise LD among the 6 marker pairs studied in the FSH receptor gene were computed, and pairs in LD (D'>0.5 or r2<0.1) are shown as gray-shaded values. c, Nucleotide sequence of the 5' upstream region of the FSH receptor gene. 
, the major transcriptional initiation site, and the first nucleotide upstream of the transcriptional initiation site is designated –1. The G/A in bold type indicates the SNP of rs1394205. The italicized ATG indicates the start codon. Underlined nucleotide sequences indicate the PCR primers for making the insert of the plasmid that was used to measure transcriptional activities. The double underline indicates the cis element of the transcription factor Ets-1.
Linkage Disequilibrium Analysis
SNPAlyze version 3.2 (DYNACOM Co, Ltd) was used for determining haplotype and linkage disequilibrium (LD) analyses and is available online at http://www.dynacom.co.jp/products/package/snpalyze/index.html (Figure 1b).
Preparation of Plasmids Including the G-Type or A-Type DNA Fragment
G-type and A-type rs1394205 reporter constructs were made. Because it has been reported that the –250-bp upstream region of this gene has a core promoter activity, 2 oligonucleotide primers, 5'-CCTTAGGTCAGGGTGTAAGAAACCC-3' (bases –202 to –226) and 5'-GGCCATAATTATGCATCCATCCACC-3' (bases +6 to –19), were designed (Figure 1c).8 These primers contain the KpnI and HindIII restriction sites, respectively. After digestion with KpnI and HindIII, PCR products were subcloned into the KpnI and HindIII sites of the luciferase reporter gene vector pGV-B2 (Tokyo Ink). The G-type and A-type constructs were verified by sequencing.
Measurement of Transcriptional Activities of G-Type and A-Type Alleles
For transfection of Chinese hamster ovary (CHO) cells with FSHR gene promoter constructs, cells (60% to 70% confluent) were preincubated in OptiMEM medium (Lipofectamine, Gibco BRL) for 30 minutes at 37°C. FSHR gene promoter plasmids (1 µg) and a plasmid containing TK-driven pRL (Toyo Ink, 200 ng, used to normalize for transfection efficiency) were mixed with liposome suspension (Lipofectamine, Gibco BRL, 6 µl/well) and incubated for 20 minutes at room temperature. The lipid-coated DNA was then added to each well containing 0.8 mL of OptiMEM media. After 3 hours, the medium was removed and replaced with complete medium for an additional 48 hours. CHO cells were then lysed (400 µL), and extracts were centrifuged to remove intact cells and debris. Extracts (50 µL) were used for measurement of luciferase activity. Luciferase activity was measured 3 times in duplicate with a double luciferase assay system (PicaGene Dual SeaPansy, Toyo Ink,) and a luminometer (LB-9507, Berthold). All of the data were normalized as relative light units/pRL-TK activity.17
Serum Levels of Estradiol
We measured serum levels of estradiol in female EH patients. Seventeen subjects in the female EH group were selected randomly. All of the subjects were confirmed to be postmenopausal by their own testimony. Six patients had the A/A genotype, and 12 patients had the G/A or G/G genotypes. Serum estradiol levels were measured with the Electro Chemil Luminescence Immunoassay (Elecsys Systems Immunoassay, Roche Diagnostics), as reported previously.18
Statistical Analysis
Data are shown as mean±SD. All of the statistical analyses were conducted using StatView 5.0 (SAS Inc) and Dr. SPSS II (SPSS Inc). Hardy–Weinberg equilibrium was assessed by a 
2 analysis. The overall distributions of the genotypes or alleles were analyzed by 2 analysis using 2x3 or 2x2 contingency tables between EH patients and NT controls. To assess the quantitative effects of covariates, multiple logistic regression analysis was performed using SPSS II. Statistical significance was established at P<0.05.
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Results |
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First Case–Control Study
Table 1 shows the distribution of genotypic and allelic frequencies of the 5 SNPs in each group. The observed and expected genotypic frequencies of each of the SNPs in the total subjects, male and female, of the NT group were in good agreement with the predicted Hardy–Weinberg equilibrium values (data not shown). The overall distribution of genotype and allele of all 5 of the SNPs did not significantly differ between men for the EH and NT groups. However, among women, the genotypic and allelic frequency of rs1394205 and the allelic frequency of rs2055571 showed a significant difference between the 2 groups. For the total subjects (male and female) the genotypic and allelic frequency of rs1394205 and the genotypic frequency of rs2268361 were significantly different between the EH and NT subjects. These data indicate that the distribution of rs1394205 in women can affect the overall analysis in the total subject group. Therefore, this could be used as a genetic marker of EH in women, because the probability value for the allelic distribution of this SNP was very significant (P=0.003).
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Patterns of LD in the FSHR gene are illustrated by their D' and r2 values (Figure 1b). LD analysis for the NT group and the D' values indicate that rs1394205 and rs2055571 are located in one haplotype block, whereas the other 3 SNPs are located in another block. Because the r2 values were beyond 0.1 in rs1394205 to rs2055571, it is not advantageous to use these combinations to isolate susceptibility haplotypes.
Based on these results, rs1394205 was selected for the large-size case–control study. We were also interested in the fact that the rs1394205 may influence the transcriptional activity of the gene, because the SNP is located in the 5' upstream region.
Confirmative Case–Control Study: Subgroup Collaboration Study With the Hypertensive Section of the Japanese Millennium Project
Table 2 shows the clinical features of the EH patients and NT controls. These 2 groups were age-matched for the total, male, and female groups. We performed the confirmative case–control study for the rs1394205 SNP using 1035 EH patients and 1058 NT controls.
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The observed and expected genotypic frequencies of each of the SNPs in the total subjects (P=0.553), males (P=0.853), and females (P=0.426) of the NT group were in good agreement with the predicted Hardy–Weinberg equilibrium values. The overall distribution for the alleles of the SNPs did not significantly differ between the total EH and total NT groups. However, among women, the allelic frequency of the A allele of rs1394205 was significantly higher for EH subjects than for NT subjects (P=0.042; Table 3). Although the genotype distribution of rs1394205 among women in the first case–control study showed a significant difference, the genotype distribution in the confirmative study did not exhibit any significant difference. This discrepancy could have been caused by differences in sample size.
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Multiple logistic regression analysis in the female subjects revealed that the significant association of A/A and G/A with EH (P=0.033) remained after adjustment for confounding factors (such as age, body mass index, total cholesterol, triglyceride, high-density lipoprotein cholesterol, uric acid, and creatinine), and the calculated odds ratio was 1.68 (95% CI: 1.04 to 2.73).
Transcriptional Activities
To study transcriptional activity, we transfected CHO cells with promoter constructs of the FSHR gene. The promoter activity of the A allele was 56±8% (mean±SD) of that for the G-type allele (P=0.001; Figure 2). The rs1394205 is located in the Ets-1 site, and when there is substitution of the A-type allele from the G-type allele, the Ets-1 site vanishes (Figure 1c).
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Serum Levels of Estradiol
All of the values of the serum levels of estradiol were <32 pg/mL, because all of the subjects were postmenopausal. The values of G/G, G/A, and A/A genotypes were 19.8±2.1, 20.5±6.2, and 13.3±3.2, respectively. Because there was no difference between the G/G and G/A genotypes (P=0.807), Figure 3 only shows the serum levels of estradiol in postmenopausal EH patients with and without the A/A genotype. Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We performed 2 genetic case–control studies in different populations for the FSHR gene and found that 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. Very recently it has been reported that knockout mice can be used as a model of postmenopausal hypertension with low levels of estrogen and high levels of testosterone.14 This report is consistent with our results that indicate that there is both an association between the polymorphism in the FSHR gene and EH and that the levels of plasma estradiol in female EH patients with the A/A genotype are significantly lower than those in female EH patients without the genotype. Furthermore, because Ets-1 has been reported to be involved in the regulation of angiogenesis and cell growth,19,20 our findings suggest that the substitution of the A-type allele from the G-type allele of the rs1394205 leads to a decreased transcriptional activity, which is followed by a subsequent loss of the Ets-1 site. Because there have been many studies reporting that low estrogen levels are associated with hypertension in postmenopausal women,21,22 our results also may provide evidence on the etiology of
1 of the causes of hypertension in postmenopausal women. In genetic case–control studies, pseudopositive results can sometimes occur. Therefore, to improve reliability, we increased the number of samples in addition to selecting samples strictly for the purpose of removing bias associated with confounding factors. It is especially advantageous to perform case–control studies using large and different populations, because this can lead to results that have a greater likelihood of being correct. The strategy of our study was to first carry out a screening case–control study followed by a confirmative case–control study that included >1000 subjects in each group. The rs1394205 showed significant differences for both case–control studies. It should be noted that the P values for the associations determined in the present study are somewhat weak. However, in accordance with the guidelines issued for specific criteria for acceptability of association study results, the current study provides biological support (transient transfection finding) and plausibility based on knockout data in mice.23 Therefore, the larger P value could be considered to be acceptable in this case.
Some case–control studies have identified gene variants associated with gender-specific susceptibility to EH24,25; however, in general, such studies do not explain the reason for the positive gender-specific association findings. Our experiment also found significant differences only for women. In contrast to previous reports, our experiment specifically examined whether the functional mutations of the gene were clearly identified in patients with a hereditary disease in a gender-specific manner. Mutations in the FSHR gene are reported to cause hereditary hypergonadotropic ovarian failure in women but not in men. To the best of our knowledge, our study is the first to report that the causal genes of gender-specific hereditary diseases are associated with EH in a gender-specific manner.
An increasing number of reports of genome-wide scans for hypertension and blood pressure variation have been seen in the past few years.26 Some of the reports have shown that 2p, on which the FSHR gene is located, is associated with the candidate loci for EH.27–32 However, these regions are broad, and there has been no definite susceptibility gene identified in this region. Although like our study in which the strategy for identification of susceptibility genes of EH was different between the genome-wide scans and case–control studies, the final goal for identifying the causal mutation for EH was the same. Therefore, because our current findings indicate that a gene variant is related to EH, our results are thought to be worthwhile. In conclusion, an SNP in the 5'-untranslated region of the FSHR gene affected the levels of transcriptional activity and, therefore, is a susceptibility mutation of EH in women.
Perspectives
We performed 2-step case–control studies and identified that the SNP in the 5'-untranslated region of the FSHR gene affects levels of transcriptional activity, which is a susceptibility mutation of EH in women. However, there are some limitations associated with our study. It is possible that the case–control studies sometimes exhibit pseudopositive results because of sample scales or selection of the genetic markers. Further research is required to perform familial linkage studies and transmission disequilibrium tests for the purpose of confirming the reliability of the rs1394205 SNP.
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Acknowledgments |
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We thank Naoyuki Sato and Kaoru Sugama for their excellent technical assistance.
Sources of Funding
This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (15012251) from the Ministry of Education, Culture, Sports, Science and Technology.
Disclosures
None.
Received December 11, 2005; first decision January 4, 2006; accepted June 15, 2006.
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M. Coylewright, J. F. Reckelhoff, and P. Ouyang Menopause and Hypertension: An Age-Old Debate Hypertension, April 1, 2008; 51(4): 952 - 959. [Full Text] [PDF]
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B. K. Rana, P. A. Insel, S. H. Payne, K. Abel, E. Beutler, M. G. Ziegler, N. J. Schork, and D. T. O'Connor Population-Based Sample Reveals Gene-Gender Interactions in Blood Pressure in White Americans Hypertension, January 1, 2007; 49(1): 96 - 106. [Abstract] [Full Text] [PDF]
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