Haplotype-Based Case-Control Study of Estrogen Receptor α (ESR1) Gene and Pregnancy-Induced Hypertension

221 Hypertens Res Vol.31 (2008) No.2 p.221-228 Original Article Haplotype-Based Case-Control Study of Estrogen Receptor α (ESR1) Gene and Pregnancy-Induced Hypertension Masaaki TAMURA1), Tomohiro NAKAYAMA2), Ichiro SATO1), Naoyuki SATO2), Noriko IZAWA2), Mikano HISHIKI2), Yoshihiro MIZUTANI3), Kiyohide FURUYA1), and Tatsuo YAMAMOTO1) 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 α (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 rs2881766rs1643821-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 rs2881766rs1643821-rs988328 and the G-A haplotype of rs2881766-rs1643821 appear to be resistance markers of PIH. (Hypertens Res 2008; 31: 221–228) Key Words: pregnancy-induced hypertension, estrogen receptor, polymorphism, haplotype, association study Introduction Pregnancy-induced hypertension (PIH) is a common and serious complication of pregnancy. There is persuasive evidence implicating genetic factors in the genesis of PIH (1). Genetic association studies have shown both positive (2–4) and negative (5, 6) associations between PIH and genetic factors. Very few genes with a potential causative role in PIH have been identified. From the 1)Department of Obstetrics and Gynecology, 2)Division of Molecular Diagnostics, Department of Medical Research Science, and 3)Department of Ophthalmology, Nihon University School of Medicine, Tokyo, Japan. This work was supported financially by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (High-Tech Research Center, Nihon University). Address for Reprints: Tomohiro Nakayama, M.D., Division of Molecular Diagnostics, Department of Medical Research Science, Nihon University School of Medicine, Ooyaguchi-kamimachi 30–1, Itabashi-ku, Tokyo 173–8610, Japan. E-mail: Received March 30, 2007; Accepted in revised form August 24, 2007. 78 31.1 ± 6.5 (17–30–46) 57.1 23.1 ± 5.5 27.0 ± 4.1 3.7 ± 2.7 9.2 ± 6.9 34.5 ± 4.3 (24–34–42) 1,973± 901 (290–1,919–3,838) 6.6 ± 2.8 (0–8–9) 169.1 ± 25.3 (120–170–230) 102.4 ± 18.5 (68–102–162) 42.2 13/29 (44.8%) No. of subjects Age (years) Frequency of primigravidas (%) BMI before pregnancy (kg/m2) BMI immediately before delivery (kg/m2) Increase in BMI during pregnancy (kg/m2) Gain of body weight in pregnancy period (kg) Gestational weeks at delivery (weeks) Birth weight of neonates (g) Apgar score (5 min) SBP (mmHg) DBP (mmHg) Family history of hypertension (%) Past history of PIH PE 0.163 0.285 0.094 0.793 0.626 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.061 0.002 < 0.001 0.866 0.351 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.005 p value vs. non-PIH (BMI matched) 0.491 p value vs. non-PIH (all) 130 32.7 ± 8.0 (17–30–45) 56.0 22.5 ± 2.8 26.1 ± 2.5 3.8 ± 1.9 9.7 ± 4.9 38.6 ± 2.3 (26–39–41) 3,075 ± 605 (1,006–3,078–3,996) 8.6 ± 0.9 (3–9–10) 124.8 ± 22.1 (90–119–212) 75.6 ± 15.8 (48–72–140) 25.9 — BMI matched PIH 17 334.3± 7.7 (23–33–45) 30.0 24.9 ± 3.6 30.2 ± 3.8 3.6± 2.8 8.5± 7.3 36.2 ± 3.3 (29–37–40) 2,562 ± 715 (1,045–2,764–3,366) 7.7 ± 2.6 (0–9–10) 161.7 ± 17.7 (140–163–194) 99.9 ± 14.8 (80–99–130) 42.9 5/7 (71.4%) 95 31.7 ± 6.8 (17–31–46) 53.4 23.3 ± 5.3 27.5 ± 4.2 3.7 ± 2.7 9.1 ± 6.9 34.7 ± 4.2 (24–36–42) 2,078 ± 896 (290–2,086–3,838) 6.8 ± 2.8 (0–8–10) 167.8 ± 24.3 (120–170–230) 102.0 ± 17.9 (68–101–162) 42.3 18/36 (50.0%) GH 0.001 < 0.001 0.861 0.265 < 0.001 0.004 0.004 < 0.001 < 0.001 0.108 0.161 < 0.001 < 0.001 < 0.001 0.455 0.001 0.005 0.019 < 0.001 < 0.001 0.255 0.435 p value vs. non-PIH (BMI matched) 0.050 0.009 0.745 0.536 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.046 < 0.001 < 0.001 0.843 0.267 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.003 p value vs. non-PIH (all) 0.358 p value vs. non-PIH (BMI matched) 0.938 p value vs. non-PIH (all) PIH PIH (all) PIH, pregnancy induced hypertension; PE, preeclampsia; GH, gestational hypertension; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure. p values were calculated between all non-PIH subjects and each PIH group. The values in parentheses are minimal values, medians and maximal values. 200 31.8 ± 7.0 (17–30–46) 56.5 21.0 ± 3.2 24.7 ± 2.7 3.7 ± 2.0 9.1 ± 6.9 38.5 ± 2.0 (26–39–41) 3,004 ± 521 (1,230–3,078–3,996) 8.6 ± 0.8 (3–9–10) 121.1 ± 20.3 (90–119–212) 74.6 ± 13.7 (48–72–135) 23.5 — All Non-PIH No. of subjects Age (years) Frequency of primigravidas (%) BMI before pregnancy (kg/m2) BMI immediately before delivery (kg/m2) Increase in BMI during pregnancy (kg/m2) Gain of body weight in pregnancy period (kg) Gestational weeks at delivery (weeks) Birth weight of neonates (g) Apgar score (5 min) SBP (mmHg) DBP (mmHg) Family history of hypertension (%) Past history of PIH Table 1. Characteristics of Study Participants 222 Hypertens Res Vol. 31, No. 2 (2008) Tamura et al: Estrogen Receptor α and Pregnancy-Induced Hypertension Steroid hormones regulate a wide range of cellular events by activating a receptor family of transcription factors. Estrogens, which are steroid hormones, can have systemic effects, including effects on the brain, heart, liver, and cardiovascular system (7). Effects of estrogens on their target tissues occur via activation of one or both of the two estrogen receptors, ERα (ESR1) and ERβ (ESR2), which are members of the nuclear receptor superfamily (8, 9). Both receptors are expressed in a wide range of tissues, including macrophages, vascular smooth muscle, and vascular endothelial cells (10). Estrogen receptors have been studied intensely within the field of female reproducti (...truncated)