甲状腺功能与代谢综合征及甲功相关基因多态性的关联性研究

发布时间：2018-06-10 06:47

本文选题：甲状腺激素 + 促甲状腺激素　；参考：《第四军医大学》2016年博士论文

【摘要】：甲状腺激素对维持和调节细胞内能量平衡十分关键,同时对糖脂代谢、血压和身体成分都有着多重效应。因此,将甲状腺功能维持到正常状态对于维持机体的正常功能十分重要。能够影响体内甲状腺激素水平的因素有很多,环境中的碘的摄入和个体的遗传因素在其中占了很大比例。近些年来,随着全基因组关联性研究(GWAS)在各种疾病和人体功能领域研究的应用,人们对影响甲状腺激素水平的遗传因素有了更深的认识,很多能够影响甲状腺功能的单核苷酸多态性(SNP)位点进入了人们的视野。代谢综合征(Metabolic syndrome,MS),是以一系列心血管风险因子为代表的代谢紊乱症候群,胰岛素抵抗是其病理生理发展过程的核心特征。鉴于甲状腺激素在能量代谢中的关键作用,其水平与各种MS相关参数亦会有相关性。很多研究已经针对甲状腺功能异常和MS组分的关系进行了研究,甲状腺功能亢进和甲状腺功能减退都已被证明与胰岛素抵抗呈正相关。在过去的十年间,一些研究也对甲状腺功能正常人群中的甲状腺激素水平和MS及其组分的相关性进行了研究,但这些结果并不一致。同时,由于遗传因素能够影响甲状腺功能,因此甲状腺相关snp与机体代谢和疾病的研究也有很多,但在不同的人群中结果亦不尽相同。中国幅员辽阔,人口众多,各地的地理环境不同,人口的遗传学背景也难免具有差异。因此,本研究以陕西省流行病学调查人群为基础,为进一步明确甲状腺激素水平与ms及其组分的关系,分析相关snp对甲状腺激素乃至ms的影响,我们进行了如下五部分研究。第一部分西安人群正常甲状腺激素水平参考值范围的制定目的:在既往碘缺乏、目前碘超足量的西安地区建立甲状腺激素水平的参考值范围,同时探索影响甲状腺功能的因素。方法:本研究纳入的研究对象为2012年至2013年间,我科在西安地区进行的流行病学调查的数据库资料。共1286人参与了研究,其中717人被选择作为参考值人群。研究共检测了促甲状腺激素(tsh)、游离t4(ft4)、游离t3(ft3)、t4、t3、甲状腺过氧化物酶抗体(tpo-ab)和甲状腺球蛋白抗体(tg-ab),同时还进行了甲状腺超声的检查。结果:新建立的甲状腺激素水平参考值范围为:tsh:0.43-5.51miu/l;ft4:11.0-20.4pmol/l,ft3:3.63-5.73pmol/l,t4:67.8-157mmol/l,t3:1.08-2.20mmol/l,与试剂供应商提供的数据有所不同。ft3水平在不同年龄组间具有显著的统计学差异(p0.05),而tsh、ft4、t4水平则在不同年龄间没有显著差异(p0.05)。男性的ft3、ft4和t3水平均高于女性(p0.05)。甲状腺超声异常组和抗甲状腺自身抗体阳性组的tsh水平高于参考值人群。结论:我们的研究为中国西部人群诊断甲状腺疾病提供了有意义的参考值范围。考虑到中国大部分内陆地区都经历了一个从碘缺乏到碘超足量的转变,我们建议在中国与西安有相似碘营养状况的地区都采用我们的参考值范围。第二部分陕西人群正常范围内甲状腺功能与代谢综合征的横断面研究目的:通过横断面研究分析正常范围内甲状腺激素水平与ms及其组分间的相关关系。方法:本部分的研究对象为2007年至2008年中国糖尿病及代谢紊乱研究中陕西省部分的人群。所有受试者均进行了体格检查、体脂百分比检测、心电图检查,完成了ogtt试验或馒头餐试餐试验,检测了血脂、血糖、胰岛素、甲状腺激素水平,完成了标准化的调查问卷。先将人群以甲状腺功能分组,比较了亚临床甲状腺异常组与正常组间ms及其组分的差别,后将甲状腺激素水平正常的人群按ft4水平三分位分组,比较各组间ms及相关组分的差异。最后以甲状腺激素水平为自变量,ms组分为因变量,分别进行了多元线性回归和logistic回归分析,分析甲状腺激素和ms的相关关系。结果:研究共纳入参与者2991名,其中亚临床甲状腺功能亢进症76名,亚临床甲状腺功能减退症121名,亚临床甲状腺功能异常对总的ms发生率没有统计学差异(p0.05)。在甲状腺功能正常人群中,sbp、dbp、fbg、fins、aucglu、aucins、homa-ir、tc、ldl-c、tg等均随ft4水平升高而升高,而hdl-c水平随ft4水平升高而降低(p0.01);随ft4水平的升高,ms和腹型肥胖、高血糖、高血压、高tg和低hdl-c的发生率均逐步升高(p0.01)。logistic回归结果显示,与第一分位相比,ms在ft4、ft3第三分位发生风险较高(orft4:2.48,95%cift4:1.93-3.17;orft3:1.94,95%cift3:1.45-2.58),在ft3/ft4比值第三分位发生风险较低(or:0.52,95%ci:0.41-0.66);在tsh第三分位发生风险有升高趋势,但无统计学差异(or:1.26,95%ci:0.99-1.59)。结论:本次横断面研究结果显示不同亚临床甲状腺功能异常状态对总的ms发生率没有显著的影响。在甲状腺功能正常人群中,ms与其相关组分与ft4、ft3水平呈正相关,与ft3/ft4比值水平呈负相关,与tsh水平无显著相关性。第三部分:陕西人群正常范围内甲状腺功能与代谢综合征组分的随访研究目的:通过随访研究分析正常范围内甲状腺功能与代谢综合征组分的相关性。方法:本部分的基线研究对象为2007年至2008年中国糖尿病及代谢紊乱研究中陕西省部分的人群,2012年至2013年间对该部分人群进行了5年后的随访。在这两次流行病学调查,所有受试者均进行了体格检查、体脂百分比检测、心电图检查,完成了ogtt试验或馒头餐试餐试验,检测了血脂、血糖、胰岛素、甲状腺激素水平,完成了标准化的调查问卷。以ms相关参数的变化值为自变量,甲状腺激素水平的变化值为因变量,进行了多元线性回归分析,分析ms相关参数的变化与甲状腺激素水平变化间的相关关系。结果:本研究共纳入符合条件的随访对象668人。多元线性回归分析结果显示,腰围、体脂百分比、bmi及ldl-c的变化与ft3的变化呈正相关(p0.05);体脂百分比、sbp、dbp、tc、ldl-c及fbg的变化与ft4的变化呈正相关;腰围、bmi的变化量与ft3/ft4比值的变化量呈正相关(p0.05),而体脂百分比、sbp、hdl-c和fbg的变化量与ft3/ft4比值的变化量呈负相关;代谢参数的变化与tsh的变化的相关性均无统计学意义(p0.05);腰围、sbp、dbp的改变与t3的改变呈正相关(p0.05);bmi、tc、tg改变与t4的改变呈负相关(p0.05)。结论:本次随访研究结果显示部分代谢相关指标的变化与ft3、ft4、ft3/ft4比值、t3和t4的变化有相关性,而与tsh的变化无显著相关性。提示代谢参数的变化可能会导致甲状腺激素水平在正常范围内波动。第四部分陕西人群甲状腺相关基因多态性与甲状腺功能的相关性目的:在陕西省人群中评价甲状腺相关基因多态性与甲状腺激素水平的关系。方法:本部分的研究对象为2007年至2008年中国糖尿病及代谢紊乱研究中陕西省部分的人群,利用massarray分子量阵列技术对甲状腺相关遗传多态性位点rs10032216、rs753760、rs10799824、rs2046045和rs2235544的基因型分布情况进行检测。比较不同位点各基因型之间甲状腺激素和tsh水平的差异。并以各snp位点的等位基因为自变量,甲状腺激素和tsh水平为因变量,利用多元线性回归分析不同等位基因与甲状腺激素和tsh水平的相关性。结果:本研究共纳入研究对象2486人。dio1基因rs2235544位点次要等位基因a的携带者ft4和t4水平随碱基a的出现而升高,ft3和ft3/ft4比值水平随碱基a的出现而降低(p0.05)。在nr3c2基因rs10032216位点、pde8b基因rs2046045位点、pde10a基因rs753760位点,tsh水平随次要等位基因的出现而降低(p0.05)而ft3、ft4、ft3/ft4比值、t3、t4水平在不同基因型间均无统计学差异(p0.05)。capzb基因rs10799824位点,tsh、ft3、ft4、ft3/ft4比值、t3、t4水平在不同基因型间均无统计学差异(p0.05)。结论:在中国陕西汉族人群中,dio1基因rs2235544位点与循环中ft3、ft4水平有显著相关性,nr3c2基因rs10032216位点、pde8b基因rs2046045位点、pde10a基因rs753760位点与血清中tsh水平显著相关,而capzb基因rs10799824位点与甲状腺激素和tsh水平无相关性。第五部分陕西人群dio1基因多态性与代谢综合征的相关性分析目的:在陕西省人群中评价甲状腺1型脱碘酶dio1基因多态性与ms及其组分间的关系。方法:本部分的研究对象为2007年至2008年中国糖尿病及代谢紊乱研究中陕西省部分的人群,通过massarray分子量阵列技术对dio1基因rs2235544的基因型分布情况进行检测。应用病例对照研究,选取人群中ms患者和健康对照,比较各组间基因型分布的差异。利用pearson卡方检验分析病例组和对照组基因型频率的差别,应用logistic回归分析rs2235544位点与ms及其组分间的相关关系,应用协方差分析比较代谢相关参数在不同基因型间的差别,应用多元线性回归分析该位点与代谢相关参数的相关性。结果:dio1基因rs2235544位点次要等位基因a在ms组的发生率较高,和对照组相比具有统计学差异(p0.01)。logistic回归分析结果显示,在显性模型中,等位基因a的显性基因型c/a-a/a与ms的患病率显著相关(or=1.38,p=0.039)。协方差分析结果显示,tg在不同基因型间具有统计学差异(p=0.045),而其他参数在不同基因型间无统计学差异(p0.05)。对rs2235544位点的加性模型进行多元线性回归,结果显示校正了性别和年龄后,空腹胰岛素(fins)和homa-ir与等位基因a的出现呈正相关,且具有统计学意义(p0.05)。在分别进一步校正bmi和homa-ir后,其正相关的统计学意义消失(p0.05)。结论:在陕西人群中,DIO1基因rs2235544位点多态性与MS发生风险的增加明显相关,其机制可能与胰岛素抵抗增强有关。然而,该观点还需要在其他人群中进行验证。
[Abstract]:Thyroid hormones are crucial for maintaining and regulating energy balance in cells, and have multiple effects on glycolipid metabolism, blood pressure and body composition. Therefore, the maintenance of thyroid function to normal state is important for maintaining the normal function of the body. There are many factors that can affect the level of thyroid gland hormone in the body. In recent years, with the application of whole genome association study (GWAS) in the research of various diseases and human functions, people have a deeper understanding of the genetic factors affecting the thyroid hormone levels and a lot of single nucleotide polymorphisms (SNP) that can affect the thyroid function. Metabolic syndrome (MS) is a metabolic disorder characterized by a series of cardiovascular risk factors. Insulin resistance is the core feature of its pathophysiological process. In view of the key role of thyroid hormone in energy metabolism, its level is also associated with various MS related parameters. Many studies have studied the relationship between abnormal thyroid function and MS components. Hyperthyroidism and hypothyroidism have been shown to be positively related to insulin resistance. In the past ten years, some studies have also shown the levels of thyroid hormones and MS and their components in normal thyroid function population. The results are not consistent, but the results are not consistent. At the same time, because genetic factors can affect thyroid function, there are many studies on thyroid related SNP and body metabolism and disease, but the results are not the same in different populations. China has a vast territory, a large population, different geographical environment and population genetics. The background is also unavoidable. Therefore, based on the epidemiological survey of Shaanxi Province, to further clarify the relationship between thyroid hormone level and MS and its components, the effects of SNP on thyroid hormone and MS are analyzed. We have carried out the following five parts. Part one, normal thyroid hormone levels in Xi'an population Objective: to establish the range of reference values of thyroid hormone levels in the past iodine deficiency and the current iodine excess in Xi'an, and to explore the factors affecting the thyroid function. Methods: the object of this study was the database of epidemiological surveys conducted in the Xi'an area from 2012 to 2013. A total of 1286 people were involved in the study, of which 717 were selected as a reference group. A total of thyroid stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), T4, T3, thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (tg-ab) were detected. Thyroid hormone water was also examined at the same time. Results: newly established thyroid hormone water The range of reference values was tsh:0.43-5.51miu/l; ft4:11.0-20.4pmol/l, ft3:3.63-5.73pmol/l, t4:67.8-157mmol/l, t3:1.08-2.20mmol/l, and the data provided by the Reagent Suppliers had significant statistical differences between different age groups (P0.05), while TSH, FT4 and T4 levels were not significantly different between different ages (P0.05). Men's FT3, FT4, and T3 levels were higher than women (P0.05). The TSH levels in the thyroid ultrasound group and the anti thyroid autoantibody positive group were higher than those of the reference group. Conclusion: our study provides a meaningful reference range for the diagnosis of thyroid disease in Western China. From iodine deficiency to iodine excess, we suggest that we use our reference range in areas with similar iodine nutritional status in China and Xi'an. Second part of the cross-sectional study of thyroid function and metabolic syndrome in the normal range of Shaanxi population: a cross-sectional study of thyroid hormone levels and MS in the normal range Methods: the subjects of this part were the population of Shaanxi Province in the study of diabetes and metabolic disorders in China from 2007 to 2008. All the subjects performed physical examination, body fat percentage test, electrocardiogram examination, completed the OGTT test or steamed bread meal test, and tested the blood lipid, blood sugar, islet. A standardized questionnaire was completed for the level of thyroid hormone. First, the population was grouped with thyroid function, and the difference of MS and its components between the subclinical thyroidism group and the normal group was compared. Then the group with normal thyroid hormone level was divided into three subgroups at the level of FT4, compared with the MS and the related components in each group. Adenoid hormone level was the independent variable, MS group was divided into dependent variables, multiple linear regression and logistic regression analysis were carried out to analyze the correlation between thyroid hormone and MS. Results: the study included 2991 participants, including 76 subclinical hyperthyroidism, 121 subclinical hypothyroidism, subclinical thyroid dysfunction. There was no significant difference in the incidence of total MS (P0.05). In normal thyroid function population, SBP, DBP, FBG, fins, aucglu, AUCIns, HOMA-IR, TC, LDL-C, TG, etc. The incidence of P0.01.Logistic regression showed that the risk of MS at FT4, FT3 third division was higher (orft4:2.48,95%cift4:1.93-3.17; orft3:1.94,95%cift3:1.45-2.58), and the risk of ft3/ft4 ratio third was lower (or: 0.52,95%ci:0.41-0.66), and the risk of occurrence in TSH third was higher than that of the first division. There was no statistical difference (or:1.26,95%ci:0.99-1.59). Conclusion: the results of this cross-sectional study showed that different subclinical thyroid dysfunction had no significant influence on the incidence of total MS. In normal thyroid function population, MS and its related components were positively correlated with FT4, FT3 water level, and negative correlation with ft3/ft4 ratio, and TSH No significant correlation. Third part: follow up study of thyroid function and metabolic syndrome in the normal range of Shaanxi population. Follow up study to analyze the correlation between thyroid function and metabolic syndrome in normal range. Methods: this part of the baseline study was on diabetes and metabolism in China from 2007 to 2008. In the study of the disorder, some people from Shaanxi province were followed up for 5 years from 2012 to 2013. In these two epidemiological surveys, all subjects performed physical examination, body fat percentage test, electrocardiogram examination, completed the OGTT test or steamed bread meal test, and detected blood lipids, blood sugar, insulin, thyroid gland. A standardized questionnaire was completed. The variation value of MS related parameters was the independent variable. The variation value of thyroid hormone level was the dependent variable. The multivariate linear regression analysis was carried out to analyze the correlation between the changes of MS related parameters and the changes of thyroid hormone levels. Results: the results were included in the eligible follow-up subjects. The results of multivariate linear regression analysis showed that the changes in waist circumference, body fat percentage, BMI and LDL-C were positively correlated with the changes of FT3, and the changes of body fat percentage, SBP, DBP, TC, LDL-C and FBG were positively correlated with the changes of FT4; the changes in waist circumference and BMI were positively correlated with the variation of ft3/ft4 ratio, and the percentage of body fat The change of BG was negatively correlated with the change of ft3/ft4 ratio, and there was no significant correlation between the changes of metabolic parameters and the changes of TSH (P0.05); the changes in waist circumference, SBP, DBP were positively correlated with the changes of T3; BMI, TC, TG changes were negatively correlated with the changes of T4. Conclusion: the results of this follow-up study showed partial metabolic related indicators. The changes in FT3, FT4, ft3/ft4, T3 and T4 were correlated, but there was no significant correlation with the changes of TSH. It was suggested that the changes in metabolic parameters may lead to the fluctuation of thyroid hormone levels in the normal range. Fourth the correlation of thyroid related gene polymorphisms in Shaanxi population and thyroid function: in Shaanxi province population The relationship between thyroid related gene polymorphism and thyroid hormone levels was evaluated. Methods: the subjects of this part were the population of Shaanxi province in the study of diabetes and metabolic disorders in China from 2007 to 2008. Massarray molecular weight array technique was used for thyroid related genetic polymorphisms rs10032216, rs753760, rs10799824, rs204. The genotypic distribution of 6045 and rs2235544 was detected. The differences in thyroid hormones and TSH levels between different genotypes of different loci were compared. The alleles of each SNP locus were taken as independent variables, thyroid hormones and TSH levels were the dependent variables, and the correlation of different alleles with thyroid hormones and TSH levels was analyzed by multiple linear regression. Results: the level of FT4 and T4 increased with the presence of base a, and the level of FT3 and ft3/ft4 decreased with the presence of base a (P0.05) in the study of the.Dio1 gene rs2235544 loci of the 2486 people, and the FT3 and ft3/ft4 ratio decreased with the presence of base a (P0.05). The level of FT3, FT4, ft3/ft4, T3, T4 in different genotypes was not statistically different (P0.05).Capzb gene rs10799824 loci, TSH, FT3, FT4, and the ratio between the different genotypes. Conclusion: in the Han population of Shaanxi, Shaanxi, China There is a significant correlation between the rs2235544 locus and the level of FT3 and FT4 in the cycle. The nr3c2 gene rs10032216 site, the rs2046045 locus of the pde8b gene, the rs753760 locus of the pde10a gene and the TSH level in the serum are significantly related, while the capzb gene rs10799824 loci are not related to the thyroid hormone and the level. The fifth part of the Shaanxi population is polymorphic and generation. The correlation analysis of the Xie syndrome Objective: To evaluate the relationship between the polymorphisms of thyroid 1 deiodidan dio1 gene and MS and its components in the population of Shaanxi province. Methods: the object of this study was the population of Shaanxi Province in the study of diabetes and metabolic disorders in China from 2007 to 2008, and the dio1 gene was detected by massarray molecular weight array technology. The genotype distribution of rs2235544 was detected. A case-control study was used to select MS patients and healthy controls to compare the differences in genotype distribution among the groups. The difference between the genotype frequencies of the case group and the control group was analyzed by the Pearson chi square test, and the correlation between the rs2235544 site and the MS and its components was analyzed by logistic regression. Covariance analysis was used to compare the differences of metabolic parameters in different genotypes. The correlation between the site and metabolic parameters was analyzed by multiple linear regression. Results: the incidence of secondary allele A in the rs2235544 site of dio1 gene was higher in the MS group than in the control group (P0.01).Logistic regression score. The results showed that in the dominant model, the dominant genotype c/a-a/a of the allele A was significantly correlated with the prevalence of MS (or=1.38, p=0.039). The covariance analysis showed that TG had statistical differences between different genotypes (p=0.045), but the other parameters were not statistically different in different genotypes (P0.05). The additive model to the rs2235544 locus was the additive model. After multiple linear regression, the results showed that there was a positive correlation between fasting insulin (fins) and HOMA-IR and the occurrence of allele A after correction of sex and age, and had statistical significance (P0.05). The statistical significance of the positive correlation was disappeared after the further correction of BMI and HOMA-IR (P0.05). Conclusion: the rs2235544 position of DIO1 gene in the Shaanxi population. Point polymorphism is associated with an increase in the risk of MS, and its mechanism may be associated with increased insulin resistance. However, this view is also required to be verified in other populations.
【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R589

【相似文献】