基因多态性与青海妊娠高血压疾病的相关性

王香林 赵得雄 庄文婷 李红荣 李建华* 代冬芳*

doi:10.16098/j.issn.0529-1356.2018.03.018

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解剖学报 ›› 2018, Vol. 49 ›› Issue (3) : 379-386. DOI: 10.16098/j.issn.0529-1356.2018.03.018

人类学

基因多态性与青海妊娠高血压疾病的相关性

王香林¹ 赵得雄² 庄文婷¹李红荣¹ 李建华^1* 代冬芳^1*

作者信息 +

Correlation between genetic polymorphism and hypertensive disorder complicating pregnancy in Qinghai

WANG Xiang-lin¹ ZHAO De-xiong² ZHUANG Wen-ting¹ LI Hong-rong¹ LI Jian-hua ^1* DAI Dong-fang ^1*

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摘要

目的探讨内皮型一氧化氮合酶（eNOS）、肿瘤坏死超家族成员13B（TNFSF13B）、缺氧诱导因子 1α（HIF-1α）、血管内皮生长因子A（VEGFA）、血管内皮生长因子受体1（VEGFR1）的基因多态性与青海孕产妇HDCP易感性的相关性。方法采用病例对照研究，120例HDCP孕产妇为研究组，同期100例健康孕产妇为对照组，所有研究对象均来自青海省。使用Sequenom MassARRAY 法检测研究对象HIF-1α基因SNP位点 RS 11549465、RS 115494657和RS 2057482；TNFSF13B基因SNP位点RS 16972194；eNOS基因SNP位点RS 2070744；VEGFA基因SNP位点RS 3025029和RS 2010963；VEGFR1基因SNP位点RS 7335588、RS 722503和RS 12584067基因型分布，比较各SNP位点在两组间的差异。结果 eNOS基因、VEGFA基因和VEGFR1基因各SNP位点在两组之间差异有显著性(P<0.001或P<0.05）。位点RS 2070744和RS 3025039基因型CC在研究组的比例均高于对照组（均P<0.001）；其中，等位基因C在HDCP人群中发病风险度（OR）分别为:2.13（1.45～3.12）和4.95（2.97～8.26）（均P<0.001）。位点RS 2010963和RS 7335588基因型GG在研究组中比例均低于对照组（均P<0.05）；此两个位点等位基因G在HDCP人群中发病风险度（OR）分别为0.50（0.34～0.74）和0.46（0.30～0.72）（均P<0.001）。位点RS 722503基因型TC在研究组的比例为56.67％，高于对照组的29.00％；等位基因C在人群HDCP发病风险度为2.46（1.58～3.84）（P<0.001）。结论 VEGFA、VEGFR1和eNOS的基因多态性与青海妊娠高血压疾病有一定的关联，是该病在青海发病率高的潜在遗传易感基因。

Abstract

Objective To explore the correlation between the polymorphisms in endothelial nitric oxide synthase(eNOS), tumor necrosis super family member 13B(TNFSF13B), hypoxia inducible factor-1α(HIF-1α), vascular endothelial growth factor A(VEGFA) and vascular endothelial growth factor receptor 1(VEGFR1) and susceptibility to hypertensive disorder complicating pregnancy (HDCP) of pregnant women in Qinghai. Methods With the performance of a case-control study, a total of 120 Han patients with HDCP were enrolled as the study group, and 100 healthy pregnant women were included as the control group during the same period. All subjects were from Qinghai province. Sequenom MassARRAY assay was utilized to detect the genotypes of ten clinically relevant polymorphisms of HIF-1 α (RS 11549465, RS 115494657 and RS 2057482), TNFSF13B (RS 16972194), eNOS (RS 2070744), VEGFA (RS 3025029 and RS 2010963) and VEGFR1 (RS 7335588, RS 722503 and RS 12584067). Besides, the differences of single nucleotide polymorphism (SNP) sites were compared between groups subsequently. Results eNOS gene, VEGFA gene,and VEGFR1 gene were found to be significantly different between the study group and the normal group (P<0.001 or P<0.05).The proportions of genotype CC in RS 2070744 and RS 3025039 were higher in the study group than those in the control group (all P<0.001). Among them, the odd ratio (OR) of C allele in the two loci were 2.13 (1.45-3.12) and 4.95 (2.97-8.26) in the HDCP population (all P<0.001), respectively.The proportions of genotype GG in RS 2010963 and RS 7335588 were lower in the study group than those in control group (all P<0.05). Meanwhile, the OR of G alleles in the two loci were 0.50 (0.34-0.74) and 0.46 (0.30-0.72) in the HDCP population (all P<0.001), respectively. Furthermore, the proportion of RS 722503 genotype TC in the study group was 56.67%, higher than that of the control group of 29%, and the OR of C allele was 2.46 (1.58-3.84) in the population HDCP (P<0.001). Conclusion The genetic polymorphisms of VEGFA, VEGFR1 and eNOS are associated with HDCP in Qinghai province, which may be the potential genetic risk factors inducing high incidence of the disease in Qinghai.

导出引用

王香林赵得雄庄文婷李红荣李建华代冬芳. 基因多态性与青海妊娠高血压疾病的相关性[J]. 解剖学报. 2018, 49(3): 379-386 https://doi.org/10.16098/j.issn.0529-1356.2018.03.018

WANG Xiang-lin ZHAO De-xiong ZHUANG Wen-ting LI Hong-rong LI Jian-hua DAI Dong-fang. Correlation between genetic polymorphism and hypertensive disorder complicating pregnancy in Qinghai[J]. Acta Anatomica Sinica. 2018, 49(3): 379-386 https://doi.org/10.16098/j.issn.0529-1356.2018.03.018

参考文献

［1］Hromadnikova I, Kotlabova K, Hympanova L, et al. Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood.［J］. Thromb Res, 2016, 137:126-140.

［2］Liao YX, Wang ChH. The application of magnesium sulfate and antihypertensive drugs for hypertensive disorder complicating pregnancy［J］. Chinese Journal of Family Planning & Gynecotokology, 2016, 8(5):6-8. (in Chinese)

廖运先, 王晨虹. 妊娠期高血压疾病硫酸镁及降压药的应用［J］. 中国计划生育和妇产科, 2016, 8(5):6-8.

［3］Deng L, Fang BM. Clinical epidemiological analysis of hypertensive disorder complicating pregnancy［J］. Hainan Medical Journal, 2015,26(17):2602-2603. (in Chinese)

邓莉, 方碧梅. 妊娠期高血压疾病的临床流行病学分析［J］. 海南医学, 2015,26(17):2602-2603.

［4］Xiang MJ. Analysis of the correlation between the outcome of hypertensive disorder complicating pregnancy and altitude［J］. Tibetan Medicine, 2017,38(1):83-84. (in Chinese)向茂菊.关于妊娠期高血压疾病转归与海拔的相关性分析［J］.西藏医药,2017,38(1):83-84.

［5］Chen XY. Clinical analysis of severe preeclampsia in high altitude area［J］. Women’s Health Research,2017,(7):112,116. (in Chinese)

陈秀英.高海拔地区重度子痫前期临床分析［J］.中外女性健康研究,2017,(7):112,116.

［6］Gu SQ. Study on the expression of platelet membrane glycoprotein CD62P and CD63 in high altitude hypoxia environment［J］. Journal of High Altitude Medicine,2016,26(1):40-42. (in Chinese)

顾松琴. 高原低氧环境下血小板膜糖蛋白CD62P、CD63表达的研究［J］. 高原医学杂志, 2016,26(1):40-42.

［7］Deng J. Clinical analysis of 70 cases of hypertensive disorder complicating pregnancy in plateau area［J］. Medical Information,2015,(5):59. (in Chinese)

邓军.高原地区妊娠期高血压疾病70例临床分析［J］.医学信息,2015,(5):59.

［8］Zhou WT, Hu Y, Xu F, et al. Association of eNOS gene polymorphism with acute mountain sickness and sports hypoxia acclimation［J］. Journal of High Altitude Medicine, 2015, 30(3):72-75. (in Chinese)

周文婷, 胡扬, 徐飞,等. eNOS基因多态性与急性高山病低氧运动习服效果的关联研究［J］. 高原医学杂志, 2015, 30(3):72-75.

［9］Li HR, Zhang YG, Lü CX, et al. Plasma EPO level and T3541G single nucleotide polymorphisms in the 3 ’terminal hypoxic enhancer region of the Han PIH patients in Qinghai Province［J］. Shandong Medical Journal, 2017, 57(19):57-59. (in Chinese)

李红荣, 张耀刚, 吕彩霞,等. 青海省汉族PIH患者血浆EPO水平及EPO基因3’端低氧增强子区T3541G单核苷酸多态性观察［J］. 山东医药, 2017, 57(19):57-59.

［10］Zhang H, Lu C, Fang M, et al. HIF-1α activates hypoxia-induced PFKFB4 expression in human bladder cancer cells.［J］. Biochem Biophys Res Commun, 2016, 476(3):146-152.

［11］Jain A, Kratimenos P, Koutroulis I, et al. Effect of intranasally delivered rh-ⅤEGF165 on angiogenesis following cerebral hypoxia-ischemia in the cerebral cortex of newborn piglets［J］. Int J Mol Sci, 2017, 18(11):2356.

［12］Li HR. Association of eNOS, EPO and TNF-α gene polymorphisms with hypertensive disorder complicating pregnancy in Han population of Qinghai［D］. Qinghai University, 2017. (in Chinese)

李红荣. eNOS、EPO、TNF-α基因多态性与青海省汉族妊娠高血压疾病相关性研究［D］. 青海大学, 2017.

［13] Luizon MR, Sandrim VC, Palei AC, et al. Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy［J］. Hypertens Res, 2012, 35(9):917.

［14］Li W. Expression of VEGF and its receptor in placenta of pregnancy induced hypertension syndrome［J］. Cardiovascular Disease Journal of Integrated Traditional Chinese and Western Medicine (Electronic), 2015, 3(35):161. (in Chinese)

李伟. VEGF及其受体在妊娠高血压综合征胎盘的表达［J］. 中西医结合心血管病电子杂志, 2015, 3(35):161.

［15］Hu TX, Jing W, Tan QY, et al. Hydrogen sulfide inhibits high glucose-induced sFlt-1 production via decreasing ADAM17 expression in 3T3-L1 adipocytes［J］. Int J Endocrinol,2017,6(3):1-9.

［16］Semenza GL. A compendium of proteins that interact with HIF-1α［J］. Exp Cell Res, 2017, 35(6):128-135.

［17］Serebrova VN, Trifonova EA, Gabidulina TV, et al. Detection of novel genetic markers of susceptibility to preeclampsia based on an analysis of the regulatory genes in the placental tissue［J］. Mol Biol, 2016, 50(5):870-879.

［18］Kim SY, Park SY, Lim JH, et al. Hypoxia inducible factor-1α gene polymorphisms in Korean patients with pre-eclampsia［J］. J Endocrinol Invest, 2012, 35(7):670-675.

［19］Dellamorte D, Riondino S, Ferroni P, et al. Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity.［J］. Pharmacogenomics, 2015, 16(1):61-78.

［20］Po?arowska D, Po?arowski P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy［J］. Cent Eur J Immunol, 2016, 41(3):311-316.

［21］Noushin JN, Farrokh T, Zahra K. Vascular endothelial growth factor expression and vascular density in oral squamous cell carcinoma (OSCC): A study on clinical and histopathologic significance［J］. Med J Islam Repub Iran, 2016, 30(1):358.

［22］Liu L, Bi N, Wu L, et al. MicroRNA-29c functions as a tumor suppressor by targeting VEGFA in lung adenocarcinoma［J］. Mol Cancer, 2017, 16(1):50.

［23］Amosco MD, Villar VAM, Naniong JMA, et al. VEGF-A and VEGFR1 SNPs associate with preeclampsia in a Philippine population［J］. Clin Exp Hypertens, 2016, 38(7):578-585.［24］Andraweera PH, Dekker GA, Dissanavake VH, et al. Vascular endothelial growth factor family gene polymorphisms in preeclampsia in sinhalese woman in Sri-Lanka［J］. Matern Fetal Neonatal Med, 2013, 26(5):532-536.

［25］Chedraui P, Solis EJ, Bocci G, et al. Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia［J］. J Matern Fetal Neonatal Med, 2013, 26(3):226-232.

［26］Amosco MD, Villar VAM, Naniong JMA, et al. VEGF-A and VEGFR1 SNPs associate with preeclampsia in a Philippine population［J］. Clin Exp Hypertens, 2016, 38(7):578-585.［27］Ben AGM, Al-Madhi SA, Zitouni H, et al. Vascular endothelial growth factor single nucleotide polymorphisms and haplotypes in pre-eclampsia: A case-control study［J］. Cytokine, 2017, 97:175-180.

［28］El-Sonbati AZ, El-0Baz RA, Saad EA, et al. Vascular endothelial growth factor VEGF G/C 405 and C/A 2578 gene polymorphisms in cases with pre-eclampsia［J］. Int J Pharm Pharmaceut Sci, 2014, 6(10):281-284.

［29］Wu S, Hao G, Zhang S, et al. Cerebral vasoconstriction reactions and plasma levels of ETBR, ET-1, and eNOS in patients with chronic high altitude disease［J］. Mol Med Reports, 2016, 14(3):2497-2502.

［30］Xia QH. The effect of acute hypoxia at different altitudes on the expression of eNOS gene in rat myocardial tissue［D］. Qinghai University, 2013. (in Chinese)

夏庆华. 不同海拔急性低氧条件对大鼠心肌组织eNOS基因表达的影响［D］.青海大学,2013.

［31］Zhang B, Chamba Yangzom, Li QG,et al. Expression of endothelial nitric oxide synthase (eNOS) gene in Tibetan pigs and analysis of hypoxia adaptation［J］. Journal of China Agricultural University, 2013,18(5):104-108. (in Chinese)

张博, 强巴央宗, 李庆岗,等. 藏猪内皮型一氧化氮合酶(eNOS)基因的表达与低氧适应分析［J］. 中国农业大学学报, 2013, 18(5):104-108.

［32］Seremak-Mrozikiewicz A, Drews K, Barlik M, et al. The significance of-786T>C polymorphism of endothelial NO synthase (eNOS) gene in severe preeclampsia［J］. J Matern Fetal Med, 2011, 24(3):432-436.

［33］Leonardo DP, Albuquerque DM, Lanaro C, et al. Association of Nitric Oxide Synthase and Matrix Metalloprotease Single Nucleotide Polymorphisms with Preeclampsia and Its Complications.［J］. PLoS One, 2015, 10(8):e0136693.

［34］Fenstad MH, Johnson MP, Roten LT, et al. Genetic and Molecular Functional Characterization of Variants within TNFSF13B, a Positional Candidate Preeclampsia Susceptibility Gene on 13q［J］. PLoS One, 2010, 5(9):e12993.