雄激素及糖皮质激素代谢关键基因多态性与多囊卵巢综合征遗传易感性的关联研究

发布时间：2018-01-15 22:21

本文关键词：雄激素及糖皮质激素代谢关键基因多态性与多囊卵巢综合征遗传易感性的关联研究　出处：《南京医科大学》2016年博士论文　论文类型：学位论文

【摘要】：[目的]高雄激素血症是多囊卵巢综合征(PCOS)诸多临床表现中重要特征之一。17β羟基类固醇脱氢酶5型(HSD17B5)基因和17β羟基类固醇脱氢酶6型(HSD17B6)基因可以编码特殊的酶类,参与雄激素的合成和代谢,因此是雄激素合成和代谢的关键基因。本研究评价HSD17B5和HSD17B6基因的多态性与多囊卵巢综合征患者患病风险和临床表现之间的关系。[方法]收集335名PCOS患者为研究对象,对照组为354名正常妊娠妇女,利用TaqMan等位基因分型(AD)技术对这两组人群中HSD17B5 (rsl937845和rs12529)和HSD17B6 (rs898611)基因位点多态性进行检测,比较其差异性。同时测定PCOS患者基础状态下生殖内分泌、代谢指标,包括卵泡刺激素(FSH)、黄体生成素(LH)、雌二醇(E2)、睾酮(T)、泌乳素(PRL)、空腹血糖(Fasting glucose)、空腹胰岛素(Fasting insulin)、硫酸脱氢表雄酮(DHEAS),利用Stata软件进行统计分析,对比PCOS组与对照组基因位点多态性之间的差异性,分析PCOS组临床生化结果与各基因位点多态性之间的相关性。[结果]我们发现HSD17B5基因rs1937845位点各基因型分布在PCOS组和对照组中存在显著性差异,该位点CT基因型和T等位基因在PCOS组分布显著高于对照组(P=-0.002,P=-0.012),说明HSD17B5基因rs1937845位点CT基因型和T等位基因是PCOS的易感基因。我们比较PCOS患者临床内分泌指标与HSD17B5和HSD17B6各多态位点之间的关系,发现HSD17B5基因rs12529位点CC基因型血睾酮水平显著高于GG基因型(P=-0.034)；该基因rs1937845位点TT基因型睾酮水平高于CC基因型(P=-0.053),且该位点TT基因型稳态模型胰岛素分泌指数(HOMA-B%)显著高于CC基因型(P=-0.045)。将PCOS组按睾酮水平的高低分为高雄激素血症组和非高雄激素血症组,分析各SNP位点多态性与高雄激素血症之间的关系,我们发现HSD17B5rs12529位点GC基因型(P=-0.054)和C等位基因(P=-0.002)及rs1937845位点CT基因型(P=-0.047)和T等位基因(P=-0.004)与高雄激素血症均密切相关。未发现HSD17B6基因rs898611位点基因多态性与PCOS患病风险之间的相关性。[结论]本研究提示HSD17B5基因rs 1937845位点基因多态性与PCOS遗传易感性相关,该位点CT基因型与T等位基因可增加罹患PCOS的风险。HSD17B5可能参与了雄激素的代谢调节,该基因rs12529位点GC基因型和C等位基因和rs1937845位点CT基因型和T等位基因增加了PCOS患者罹患高雄激素血症的风险。未发现HSD17B6基因rs898611位点多态性与PCOS遗传易感性之间的关联性。[目的]PCOS患者常出现肥胖、糖耐量的异常(或糖尿病)及血清胰岛素水平的升高,人体中葡萄糖的代谢、脂肪分布及脂质代谢均有糖皮质激素参与其中并起重要作用。11β羟基类固醇脱氢酶1型(HSD11B1)是调节糖皮质激素活性的关键酶,主要表现为还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)依赖型的还原酶活性,H6PD可以催化烟酰胺腺嘌呤二核苷酸(NAD)还原为NADPH,两者协同作用影响糖皮质激素的活性,因此HSD11B1与H6PD是糖、脂代谢的关键基因。本研究探讨糖皮质激素代谢关键基因HSD11B1和H6PD基因多态性与PCOS易感性的关系。[方法]本研究中PCOS组为335名PCOS患者,对照组为354名妊娠妇女,利用TaqMan等位基因分型技术对这两组人群中HSD11B1 (rs846908)和H5PD(rs6688832和rs17368528)基因位点多态性进行检测,同时测定PCOS患者基础状态下生殖内分泌相关指标,包括FSH、LH、E2、T、PRL、空腹血糖(Fasting glucose)、空腹胰岛素(Fasting insulin)、DHEAS,利用Stata软件进行统计分析,对比PCOS组和对照组各位点基因多态性之间的差异性,分析PCOS组临床生化结果与基因多态性之间的关系。[结果]发现H6PD基因rs6688832位点多态性在PCOS组和对照组中分布存在显著差异,该位点GG基因型和G等位基因在对照组中显著高于PCOS组(P=0.045,P=0.040),说明G等位基因是保护性因素。分析各SNP位点基因型与临床内分泌指标之间的关系,我们发现PCOS患者rs6688832位点AG基因型与高雄激素血症显著相关(P=0.021),且该位点AG基因型携带者比从基因型携带者FSH水平低(P=-0.039)。将PCOS组与对照组按照年龄和体质指数(BMI)进行分组进行分层分析,结果发现,rs6688832位点在PCOS组和对照组中A与G等位基因分布频率的差异性与年龄无关而与BMI有关,在BMI23的超重人群中PCOS组G等位基因频率显著降低(P=-0.037),而在BMI≤23的人群中无显著性差异。我们未发现HSD11B1 (rs846908)位点和H6PD (rs17368528)基因位点多态性与PCOS之间存在显著关联。[结论]本研究结果提示PCOS患者H6PD基因rs6688832位点AG基因型与高雄激素血症有关,该位点G等位基因是保护性基因,这种保护性作用在超重和肥胖人群中体现更明显。
[Abstract]:[Objective] Kaohsiung is the hormone level of polycystic ovary syndrome (PCOS) in many clinical manifestations of one of the most important features of.17 beta hydroxysteroid dehydrogenase type 5 (HSD17B5) gene and 17 beta hydroxysteroid dehydrogenase type 6 (HSD17B6) gene encoding specific enzymes involved in androgen synthesis and metabolism, and therefore is the key gene and androgen synthesis metabolism. This study evaluated the polymorphisms of HSD17B5 gene and HSD17B6 gene with polycystic ovary syndrome patients. Methods relationship between risk and clinical manifestations] collected from 335 PCOS patients as the research object, the control group was 354 normal pregnant women with type TaqMan allele (AD) of HSD17B5 of the two groups the crowd (rsl937845 and rs12529) and HSD17B6 (rs898611) to detect polymorphism, and compare their differences. At the same time in patients with PCOS were measured under baseline endocrine, metabolic parameters, including eggs Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), prolactin (PRL), fasting blood glucose (Fasting glucose), fasting insulin (Fasting insulin), dehydroepiandrosterone sulfate (DHEAS), Stata software was used for statistical analysis, contrast group and PCOS the differences between the control group and gene polymorphism of PCOS were analyzed. The correlation between clinical and biochemical results with the gene polymorphism we found in the PCOS group and the control group there was a significant difference of HSD17B5 gene rs1937845 locus genotype, the CT genotype and T allele was significantly higher than that of in the PCOS control group (group P=-0.002, P=-0.012 distribution), indicating that the HSD17B5 gene rs1937845 CT genotype and T allele is a susceptible gene of PCOS. We compared the relationship between PCOS patients with HSD17B5 and HSD17B6 index of Clinical Endocrinology polymorphicloci, found HSD17B5 Because of the rs12529 genotype CC in serum testosterone levels were significantly higher than GG genotype (P=-0.034); the rs1937845 gene TT genotype higher testosterone levels than CC genotype (P=-0.053), and the TT genotype in insulin secretion index homeostasis model (HOMA-B%) was significantly higher than that of CC genotype (P=-0.045). The PCOS group according to the testosterone level the level is divided into Kaohsiung hormones group and non hormone group in Kaohsiung, analyzing the relationship between the SNP polymorphism and Kaohsiung hormone level, we found that HSD17B5rs12529 GC genotype (P=-0.054) and C allele (P= -0.002) and rs1937845 (P=-0.047) CT genotype and T allele (P=-0.004 Kaohsiung) were closely related with the hormone level. No HSD17B6 gene rs898611 polymorphism and the correlation between the risk of PCOS. Conclusion] this study suggests that HSD17B5 gene RS polymorphism with PCOS 1937845 The genetic susceptibility, CT genotype and T allele may increase the risk of the risk of PCOS.HSD17B5 may be involved in the regulation of androgen metabolism and the rs12529 gene GC genotype and C allele and rs1937845 CT genotype and T allele increased in PCOS patients in Kaohsiung suffer hormone level risk. Has been found between HSD17B6 gene rs898611 polymorphism and genetic susceptibility of PCOS Association.]PCOS patients often suffer from obesity, abnormal glucose tolerance (or diabetes) and elevated serum insulin levels, body fat distribution and glucose metabolism, lipid metabolism of glucocorticoids involved and play an important role in.11 beta hydroxy hydroxysteroid dehydrogenase type 1 (HSD11B1) is a key enzyme in the regulation of glucocorticoid activity, mainly for nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme activity was That H6PD can catalyze the nicotinamide adenine dinucleotide (NAD) reduced to NADPH, the synergistic effect of active glucocorticoid, so HSD11B1 and H6PD are the key genes of sugar, lipid metabolism. Methods in this study. The relationship between glucocorticoid metabolism key genes HSD11B1 and H6PD gene polymorphism and susceptibility to PCOS in this study in group PCOS, 335 patients with PCOS, the control group of 354 pregnant women, the use of HSD11B1 for the two groups in the typing of TaqMan allele (rs846908) and H5PD (rs6688832 and rs17368528) were used to detect gene polymorphism, simultaneous determination of relevant indicators, reproductive endocrine in patients with PCOS in basic condition, including FSH LH, E2, T, PRL (Fasting glucose), fasting blood glucose, fasting insulin (Fasting insulin), DHEAS, Stata software was used for statistical analysis, comparison between PCOS group and control group the difference between the gene polymorphism H6PD, rs6688832 gene polymorphisms have significant differences between PCOS group and control group were found in the PCOS group to analyze the relationship between the clinical biochemical results and gene polymorphism. The results, GG genotype and G allele in control group was significantly higher than that of group PCOS (P=0.045, P, =0.040) G allele is a protective factor. Analyzing the relationship between the SNP genotype and clinical endocrine index, we found that PCOS was significantly correlated with rs6688832 genotype AG and Kaohsiung hormones (P=0.021), and the genotype AG than genotype carriers from low levels of FSH (P=-0.039) and PCOS group. The control group according to the age and body mass index (BMI) were grouped into stratified analysis, results showed that the difference of rs6688832 site in PCOS group and control group in A and G allele frequency distribution has nothing to do with age and is associated with BMI in BMI23 The overweight people in PCOS group, G allele frequency was significantly decreased (P=-0.037), while no significant differences in BMI is less than or equal to 23 of the population. We found no HSD11B1 (rs846908) and H6PD (rs17368528) were correlated significantly. Conclusion] the results suggest that H6PD patients with PCOS gene rs6688832 AG genotype is associated with Kaohsiung hormones between gene polymorphism and PCOS, the G allele is a protective gene, the protective effect of more obvious in overweight and obese people.

【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R711.75

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