ERBB4基因与中国汉族女性多囊卵巢综合征的关联性研究

发布时间：2018-02-28 19:43

本文关键词： 多囊卵巢综合征(PCOS) 全基因组关联研究(GWAS) ERBB4基因单核苷酸多态性(SNP)　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景多囊卵巢综合征(Polycystic Ovary Syndrome,PCOS)是育龄期妇女最常见的具有高度异质性的生殖内分泌及代谢紊乱性疾病。临床特征主要表现为稀发排卵或无排卵、高雄激素血症以及卵巢多囊样改变,同时伴有胰岛素抵抗、肥胖,远期发生糖尿病、心血管疾病以及代谢综合征的风险增加,影响女性一生健康。全基因组关联研究(Genome-wide association study,GWAS)是发现复杂疾病致病基因的有效途径。前期,我们课题组已在中国女性中发现了11个PCOS的易感区域,这些区域多数已在欧美PCOS人群得到验证。近期,基于欧洲PCOS人群的GWAS新报道了 3个易感位点—2q34(ERRBB-4)、12q21.2(KRR1)和5q31.1(RSD50),它们与中国汉族人群PCOS的发病风险是否也存在相关性亟需证实。研究目的分析欧洲人群GWAS新发现的3个PCOS易感区域是否也与中国汉族女性PCOS的发病相关。研究方法本研究纳入了 1500例中国汉族PCOS患者和1220例年龄匹配的对照。采用TaqMan-MGB的方法对可代表这3个区域的标签单核苷酸多态位点(single-nucleotide polymorphisms,SNPs)rs1351592(2q34,ERBB4)、rs1275468(12q21.2,KRR1)和rs13164856(5q31.1,RAD50)进行基因型分型。利用哈迪温伯格平衡检验等位基因频率分布,采用不同基因型遗传分析模型包括加性模型、显性模型和隐形模型比较基因型频率。并对有统计学意义的位点进行不同基因型患者的临床指标比较,选择显性模型对PCOS患者的基因型-表型进行分析。服从正态分布的连续数值变量通过非配对t检验进行分析,不服从正态分布的连续数值变量运用曼-惠特尼U检验。研究结果位于染色体2q34的ERBB4基因SNP rs1351592的等位基因频率在病例组明显高于对照组(P=1.05×10-3),校正BMI后统计学意义更加显著(Padjusted=2.09× 1 0-4),提示ERBB4也是中国汉族PCOS的易感基因。但其它2个位点rs1275468(12q21.2,KRR1)和rs13164856(5q31.1,RAD50)的风险等位基因频率在两组间的差异并无统计学意义。进一步针对有意义的位点rs1351592进行基因型与内分泌、代谢等生化指标的相关性分析,但未发现其基因分型与内分泌和代谢指标之间具有统计学意义。研究结论欧洲PCOS人群的易感位点2q34(ERBB4)同样也是中国汉族PCOS遗传易感位点,进一步说明不同人种PCOS间存在共同的遗传发病风险。
[Abstract]:The research background of polycystic ovary syndrome (Polycystic Ovary, Syndrome, PCOS) is a disease of reproductive endocrine and metabolic disorder with a high degree of heterogeneity of the most common in women of childbearing age. The main clinical features are dilute ovulation or anovulation, Kaohsiung and hormone level of polycystic ovaries, accompanied by insulin resistance, obesity, long-term diabetes and the risk of cardiovascular disease and metabolic syndrome increased influence of female life health. A genome-wide association study (Genome-wide association study, GWAS) is the effective approach to discover the complex disease gene. Early, our research group has found that women in the China 11 PCOS susceptibility regions, these regions have been confirmed in most Europe and the United States PCOS population. Recently, based on the European PCOS GWAS group reported 3 new susceptibility loci 2q34 (ERRBB-4), 12q21.2 (KRR1) and 5q31.1 (RSD50), which The risk of PCOS and Chinese Han population whether there is correlation to confirm. The purpose of this paper is the 3 new PCOS GWAS found in European populations susceptible region is also China incidence and Han female PCOS. This study included 1500 cases of the control Chinese Han PCOS patients and 1220 age matched with TaqMan-MGB. The method of tag single nucleotide polymorphisms may represent the 3 regions (single-nucleotide, polymorphisms, SNPs) rs1351592 (2q34, ERBB4), rs1275468 (12q21.2, KRR1) and rs13164856 (5q31.1, RAD50) genotype distribution. By using the Hardy Weinberg equilibrium test allele frequency with different genotype genetic analysis models including the additive model, dominant model and contact model. Comparison of genotype frequencies and the significant loci were clinical indicators of different genotypes were compared, The selection of the dominant model genotype in patients with PCOS phenotype were analyzed. It follows the normal distribution of continuous variables by non paired t test analysis, does not obey the normal distribution of continuous variables using the Mann Whitney U test. Results the ERBB4 gene is located on chromosome 2q34 SNP rs1351592 allele frequency in case group significantly higher than the control group (P=1.05 * 10-3), statistical significance was more significant after correction for BMI (Padjusted=2.09 * 10-4), suggesting that ERBB4 is susceptible Chinese Han PCOS gene. But the other 2 loci rs1275468 (12q21.2, KRR1) and rs13164856 (5q31.1, RAD50) the risk allele frequency differences among the two groups there was no statistically significant. Further genotype and endocrine for locus rs1351592 significant, correlation analysis of biochemical metabolism, but did not find the gene type and internal secretion and metabolism Conclusion the susceptibility locus 2q34 (ERBB4) in European PCOS population is also the PCOS susceptibility locus in Chinese Han nationality, which further indicates that there is a common genetic risk among different races 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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