HNF1A基因单核苷酸多态性与多囊卵巢综合征的关联研究

发布时间：2018-03-08 07:29

本文选题：多囊卵巢综合征　切入点：HNF1A基因　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:多囊卵巢综合征(polycystic ovary syndrome,PCOS)是最常见的女性生殖内分泌疾病之一,在世界范围内影响着5%-8%的育龄期女性。多囊卵巢综合征的诊断要符合以下三条标准中的两条:临床高雄症状或生化检测高雄激素血症,稀发排卵或无排卵,卵巢呈多囊样改变。此外,多囊卵巢综合征病人患代谢综合征、2型糖尿病、心血管疾病及发生血脂异常的风险增加。目前为止,国内外研究已经发现了很多与多囊卵巢综合征发病相关的易感基因,包括THAD4、TCF7L2、Y4P1、MTNRIB等。肝细胞核因子1A(HNF1A)位于人12号染色体长臂24区,包含9个外显子。HNF1A属于HNF家族,能与多种肝脏特异表达基因的启动子结合,HNF14基因主要在肝脏、胰腺、肾脏、卵巢及睾丸中表达。此外,HNF1A是脂蛋白代谢及糖激胰岛素分泌基因的重要上游调控因子。近期研究证实,HNF14基因缺陷能导致青少年成年发病型糖尿病3型的发生且与2型糖尿病的发展相关。另有研究表明,HNF1A基因也是许多其它常见疾病及临床症状的易感基因,如冠状动脉疾病、高血压、血脂异常及血清C反应蛋白浓度异常等。这些研究结果表明HNF1A可能与多囊卵巢综合征的发病相关。一项病例对照关联研究结果显示,位于HNF14基因第一外显子的单核苷酸多态位点(SNP)rs2393791与血清C反应蛋白浓度、高血压及高甘油三酯血症相关。位于HNF145'侧翼的SNP位点rs7305618与中国人群糖尿病相关。另一项全基因组关联分析(GWAS)结果显示rs7305618与血清C反应蛋白浓度的关系紧密。因此,为了验证HNF1A与多囊卵巢综合征间是否有相关性,我们选择rs2393791和rs7305618这两个SNP位点进行分析。材料和方法:在山东大学附属生殖医院就诊的患者中招募1138例PCOS患者及1125例非PCOS对照。从实验对象外周血中提取基因组DNA,并检测血清激素及血脂水平。使用Sequenom MassARRAY系统对rs2393791及rs7305618两个单核苷酸多态位点进行基因型鉴定。结果:校正体重指数和年龄后,PCOS组和对照组rs7305618等位基因频率有显著差异(p=0.023),且携带rs7305618 CC基因型PCOS患者的血清雄激素浓度高于携带CT和TT基因型PCOS患者。结论:HNF14基因SNP位点rs7305618与汉族女性PCOS发病相关,这表明HNF14基因可能是PCOS的易感基因。
[Abstract]:Objective: polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine diseases in women. Five to eight percent of women of childbearing age are affected worldwide. The diagnosis of polycystic ovary syndrome meets two of the following three criteria: clinical hyperandrogenemia or biochemical detection, rare ovulation or anovulation. Ovarian changes are polycystic. In addition, metabolic syndrome type 2 diabetes mellitus, cardiovascular disease and the risk of dyslipidemia have increased in patients with polycystic ovary syndrome. Many susceptibility genes related to the pathogenesis of polycystic ovary syndrome (PCOS) have been found at home and abroad, including THAD4TCF7L2A4P1HNRIB and MTNRIB. HNF1A) is located in the long arm 24 region of human chromosome 12, and contains 9 exons. HNF1A belongs to the HNF family. The HNF14 gene is mainly expressed in liver, pancreas and kidney. In addition, HNF1A is an important upstream regulator of lipoprotein metabolism and glucose-induced insulin secretion gene. Recent studies have shown that HNF14 gene deficiency can lead to the development of type 3 diabetes mellitus in adolescents. Other studies have shown that the HNF1A gene is also a susceptible gene for many other common diseases and clinical symptoms. Such as coronary artery disease, hypertension, dyslipidemia and abnormal serum C-reactive protein concentration. These results suggest that HNF1A may be associated with the pathogenesis of polycystic ovary syndrome. SNPrs2393791, a single nucleotide polymorphic site located at exon 1 of HNF14 gene, is associated with serum C-reactive protein concentration. High blood pressure and hypertriglyceridemia. The SNP locus at HNF145'flanking is associated with diabetes in Chinese population. Another genome-wide association analysis (GWASs) shows that rs7305618 is closely related to serum C-reactive protein concentration. To verify the association between HNF1A and polycystic ovary syndrome, Materials and methods: 1138 PCOS patients and 1125 non-#en4# controls were recruited from the affiliated Reproductive Hospital of Shandong University. Genomic DNA was extracted from peripheral blood of the subjects. Sequenom MassARRAY system was used to identify rs2393791 and rs7305618 single nucleotide polymorphism loci. Results: the frequency of rs7305618 alleles was significantly adjusted for body mass index (BMI) and age. The serum androgen concentration of PCOS patients with rs7305618 CC genotype was higher than that of PCOS patients with CT and TT genotypes. Conclusion rs7305618 at the SNP site of the 1: HNF14 gene is associated with PCOS in Han women. This suggests that the HNF14 gene may be a susceptible gene to PCOS.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R711.75

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