Glucocorticoid synthesis-related genes: HSD11B1 and HSD11B2 in hypertensive disorders in pregnancy.

OBJECTIVE: To determine whether polymorphisms of the maternal glucocorticoid-related genes (HSD11B1 and HSD11B2) are associated with pregnancy-induced hypertension (PIH) in a haplotype-based case-control study. METHODS: A total of 166 PIH patients and 222 age-matched controls were genotyped, with two single-nucleotide polymorphisms (SNPs) for the HSD11B1 gene (rs2235543 and rs846910) and three SNPs for the HSD11B2 gene (rs12920590, rs45483293 and rs3743729) used as genetic markers. After separation into preeclampsia (PE) and gestational hypertension (GH) subgroups, PIH patients were assessed. RESULTS: Significant differences were noted between PE and control groups (p = 0.022, p = 0.034, respectively) for the frequency of genotypes and alleles for rs846910 of HSD11B1. The frequency of the AA genotype of rs846910 was significantly higher in PIH and PE groups compared to controls. Logistic regression analyses showed that this genotype was a risk factor for PIH and PE (adjusted OR 2.9, 95% CI 1.3-6.5 and adjusted OR 3.2, 95% CI 1.4-7.4, respectively). The frequency of the T-A haplotype established by rs2235543-rs846910 was also significantly higher in PIH and PE groups (p = 0.045, p = 0.042, respectively). CONCLUSION: rs846910 in the HSD11B1 gene could be a marker for hypertensive disorders during pregnancy. The T-A haplotype constructed by rs2235543-rs846910 was also a useful susceptibility marker for PIH and PE.

Estrogen synthesis genes CYP19A1, HSD3B1, and HSD3B2 in hypertensive disorders of pregnancy.

Hypertension in pregnancy is a multifactorial disorder caused by a complex combination of environmental factors and several predisposing genes. Since estrogen modulates placental vascular development, estrogen synthases are considered plausible candidate genes. The aim of this haplotype-based case-control study was to estimate whether polymorphisms of the maternal estrogen synthesis genes (CYP19A1, HSD3B1 and HSD3B2) are associated with preeclampsia (PE) and gestational hypertension (GH). To examine the genetic markers in 69 PE and 62 GH patients and in 155 age-matched, primiparous, healthy control subjects, genotyping of 5 SNPs for the CYP19A1 gene (rs1870049, rs936306, rs700518, rs700519, and rs4646), 3 SNPs for the HSD3B1 gene (rs3765945, rs6203, and rs1047303), and 2 SNPs for the HSD3B2 gene (rs2854964 and rs1819698) was performed. For rs700158 of CYP19A1, the frequencies of the AG+GG genotype and the G allele were significantly higher in PE as compared to controls (P = 0.037, P = 0.033, respectively). Logistic regression analyses indicated that the AG+GG genotype of rs700158 was a PE risk factor (odds ratio = 2.15, P = 0.026). In addition, the frequency of the G-G haplotype established by rs700518-rs4646 was also significantly higher for PE (P = 0.017). These data suggest that the estrogen synthesis gene, CYP19A1 is associated with PE in the Japanese population.

Haplotype-based case-control study of estrogen receptor alpha (ESR1) gene and pregnancy-induced hypertension.

Hypotheses about pregnancy-induced hypertension (PIH) have been proposed to explain the vascular damage that characterizes this disease. Reports indicate that estrogens and estrogen receptors play important physiological roles in cardiovascular diseases. There have been studies examining the association between coronary artery disease and the estrogen receptor alpha (ESR1) gene. The aim of the present work was to assess the association between PIH and single-nucleotide polymorphisms (SNPs) in the human ESR1 gene, by conducting a haplotype-based case-control study. Based on a database search at the web site of the National Center of Biotechnology Information, we chose five SNPs in the human ESR1 gene, and performed an association study using 95 PIH patients and 200 age-matched non-PIH subjects. The frequency of rs2881766 genotypes and alleles differed significantly between the two groups. There was no significant difference in overall distribution of genotypes or alleles of the other four SNPs. The T allele of rs2881766 was significantly more prevalent in the PIH group than in the non-PIH group. Haplotype-based case-control analysis revealed that there was a significant difference in overall distribution of the combinations rs2881766-rs1643821-rs988328 and rs2881766-rs1643821 between the PIH group and the non-PIH group (all or body mass index [BMI]-matched). One susceptibility haplotype for PIH and two resistance haplotypes for PIH were revealed by comparison between the PIH group and the non-PIH (BMI-matched) control group. In conclusion, the T allele of rs2881766 could be a useful genetic marker of PIH. The G-A-T haplotype of rs2881766-rs1643821-rs988328 and the G-A haplotype of rs2881766-rs1643821 appear to be resistance markers of PIH.

Study of association between hypertensive disorders of pregnancy and the human coagulation factor XI gene.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) are among the most common and serious complications of pregnancy. Persuasive evidence implicaties genetic factors in the genesis of HDP. The aim of the present study was to assess the association between single-nucleotide polymorphisms (SNPs) in the human coagulation factor XI (F11) gene and HDP, by conducting a haplotype-based case-control study. METHODS: We chose 3 SNPs (rs925453, rs925451, and rs12500151) in the human F11 gene as genetic markers. We then conducted an association study with 77 HDP patients and 154 age-matched non-HDP subjects. RESULTS: The frequency of rs925453 genotypes significantly differed between the two groups. The frequency of the T-G-G haplotype was significantly higher in the HDP group than in the non-HDP group (p = 0.0002). CONCLUSIONS: The T allele of rs925453 and the T-G-G haplotype appear to be useful genetic markers of HDP.

Association study between the human Renin gene and preeclampsia.

OBJECTIVE: We recently reported on a missense mutation in exon 9 of the human renin gene (G1051A) that may affect the functioning of this enzyme, and is associated with essential hypertension. The aim of the present study is to assess the association between the genotypes of this missense mutation in the renin gene and preeclampsia (PE) via a case-control study. METHODS: DNA was extracted from peripheral blood leukocytes, and genotyping of G1051A was performed in 117 PE patients and in 171 non-PE controls. RESULTS: The frequency of genotypes for G1051A was not significantly different between the two groups. The frequency of the A1051 allele was also not significantly different between PE patients (52.6%) and non-PE controls (50.6%). CONCLUSIONS: The missense mutation G1051A in the human renin gene is not associated with PE.

Association study using single nucleotide polymorphisms in the estrogen receptor beta (ESR2) gene for preeclampsia.

The pathophysiology of preeclampsia (PE) remains uncertain despite many research efforts. Actual hypotheses seek to explain the vascular damage that characterizes the disease. Recently, it was reported that the mouse disrupted estrogen receptor beta (ESR2) gene was associated with abnormal vascular function and hypertension. Moreover, some investigators have reported that subjects with a family history of hypertension have a statistically significant increased risk for PE. Thus, it is thought that the pathophysiology of PE overlaps that for hypertension. The aim of the present study was to investigate the relationships between single nucleotide polymorphisms (SNPs) in the human ESR2 gene and PE in Japanese subjects, and to assess the involvement of a family history of hypertension in these relationships. Based on a database search on the web site of the National Center of Biotechnology Information (NCBI), we chose four SNPs in the human ESR2 gene, and performed an association study in 84 PE patients and 160 age-matched non-PE subjects. The overall distribution in each SNP did not differ significantly between the two groups. However, after dividing the groups into subjects with and without a family history of hypertension, the allelic distribution of one of the SNPs (rs928554) revealed a positive association. Thus, a possible mutation linked to a SNP may prescribe a genetic predisposition for patients with a family history of hypertension in PE.