ABSTRACT
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.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics , Glucocorticoids/biosynthesis , Hypertension, Pregnancy-Induced/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Adult , Asian People/genetics , Case-Control Studies , Female , Genetic Predisposition to Disease , Glucocorticoids/genetics , Humans , Hypertension, Pregnancy-Induced/epidemiology , Hypertension, Pregnancy-Induced/metabolism , Metabolic Networks and Pathways/genetics , Polymorphism, Single Nucleotide , Pregnancy , Young AdultABSTRACT
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.
Subject(s)
Aromatase/genetics , Estrogens/biosynthesis , Hypertension, Pregnancy-Induced/enzymology , Hypertension, Pregnancy-Induced/genetics , Multienzyme Complexes/genetics , Progesterone Reductase/genetics , Steroid Isomerases/genetics , Adult , Female , Genetic Markers , Genotype , Humans , Hypertension, Pregnancy-Induced/epidemiology , Japan/epidemiology , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Pre-Eclampsia/enzymology , Pre-Eclampsia/genetics , PregnancyABSTRACT
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.
