LRP6基因多态性与2型糖尿病易感性的关联分析

发布时间：2018-10-04 18:43

【摘要】：目的探讨低密度脂蛋白受体相关蛋白6(Low density lipoprotein receptor related protein 6,LRP6)基因多态性与2型糖尿病(Type 2 diabetes mellitus,T2DM)易感性的关联,并评价基因与环境因素的交互作用与T2DM发生的关系。方法本研究采用整群抽样的方法,以自然村为基本单位,对“农村糖尿病、肥胖及生活方式(RuralDiab)”研究中年龄18岁及以上的常住居民进行问卷调查、体格检查以及血样标本的采集,选取其中18-74岁的调查对象共计1998人纳入本次分析。采用磁珠法抽提全血基因组DNA,采用Taqman荧光探针法对LRP6基因rs11054731和rs12823243位点进行基因分型。分别采用独立样本t检验和χ2检验分析连续变量和分类变量在T2DM组和非T2DM组间的分布差异;运用logistic回归模型评估LRP6基因多态性与T2DM发病的优势比(Odds ratio,OR)和95%可信区间(Confidence interval,CI);运用遗传风险评分对两个位点的联合作用进行评价;根据受试者工作特征曲线下面积的改变和净重新分类指数评价遗传因素和环境因素对T2DM的判别效能,以上分析均采用SAS9.1软件完成。运用R软件Haplo.stats数据包进行单体型分析;基因与环境间的高阶交互作用则运用多因子降维模型进行评价。结果研究对象共1998人,包括911名男性和1087名女性,T2DM组349人,非T2DM组1649人。1.性别、年龄、文化程度、职业、吸烟、饮酒、蔬菜水果摄入及体力活动在T2DM组和非T2DM组分布差异均具有统计学意义(P0.05)。T2DM组腰围、BMI、收缩压、舒张压、脉压差、脉搏、总胆固醇、甘油三酯、低密度脂蛋白胆固醇和空腹血糖水平均高于非T2DM组;高密度脂蛋白胆固醇水平低于T2DM组,差异具有统计学意义(P0.001)。2.LRP6基因rs11054731和rs12823243位点的基因型及等位基因分布频率在T2DM组和非T2DM组中无统计学差异。调整协变量之前,rs11054731和rs12823243位点多态性和T2DM易感性之间未发现统计学关联(P0.05)。调整性别、年龄、吸烟、饮酒、高脂饮食、蔬菜水果摄入、体力活动、T2DM家族史和BMI后,对于rs11054731位点,携带AG基因型的人群发生T2DM的风险是1.54(1.01-2.36)。3.单体型分析发现,rs11054731和rs12823243位点GA、AT、AA、GT四种单体型在T2DM组和非T2DM组的频率分布无差异,且和T2DM易感性无统计学关联(P0.05)。未发现遗传风险评分与T2DM发生之间存在关联。4.三种模型中,与仅考虑环境因素相比,纳入遗传因素后净重新分类指数分别为3.06%、2.50%、0.79%,但对T2DM判别效能的改变不具有统计学意义(P0.05)。rs11054731和rs12823243位点与环境因素在T2DM易感性中未发现交互作用。结论本研究人群中,LRP6基因rs11054731位点AG基因型能够增加T2DM发病风险。LRP6基因两个位点的单体型和遗传风险评分与T2DM的易感性之间未发现存在关联。LRP6基因与环境因素在T2DM的发生中未发现存在交互作用。
[Abstract]:Objective to investigate the association of low density lipoprotein receptor associated protein (6 (Low density lipoprotein receptor related protein 6) LRP6) polymorphism with susceptibility to type 2 diabetes mellitus (Type 2 diabetes mellitus,T2DM), and to evaluate the relationship between gene interaction with environmental factors and T2DM. Methods A cluster sampling method was used to investigate the residents aged 18 years and over in the study of "Rural Diabetes, Obesity and lifestyle (RuralDiab)", using natural villages as the basic unit. A total of 1998 subjects aged 18-74 were selected for physical examination and blood sample collection. The genomic DNA, of whole blood was extracted by magnetic bead method. The rs11054731 and rs12823243 loci of LRP6 gene were genotyped by Taqman fluorescence probe method. T test and 蠂 2 test were used to analyze the distribution difference between T2DM group and non T2DM group. Logistic regression model was used to evaluate the odds ratio (Odds ratio,OR) and 95% confidence interval (Confidence interval,CI) of LRP6 gene polymorphism to T2DM, and the combined effect of the two loci was evaluated by genetic risk score. According to the change of area under the operating characteristic curve and the net re-classification index, the discriminant effectiveness of genetic and environmental factors to T2DM was evaluated. The above analysis was completed by SAS9.1 software. The haplotype analysis is carried out with R software Haplo.stats packet, and the high-order interaction between gene and environment is evaluated by multi-factor dimensionality reduction model. Results A total of 1998 subjects, including 911 males and 1087 females, were enrolled in T2DM group (349 subjects) and non T2DM group (1649 subjects). Sex, age, education, occupation, smoking, drinking, vegetable and fruit intake and physical activity were significantly different in T2DM group and non-T2DM group (P0.05). T2DM group had significant differences in waist circumference, systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol. The levels of triglyceride, low density lipoprotein cholesterol and fasting blood glucose were higher than those of non T2DM group, and the level of high density lipoprotein cholesterol was lower than that of T2DM group. The difference was statistically significant (P0.001) .2.There was no significant difference in genotype and allele distribution of rs11054731 and rs12823243 loci between T2DM group and non-T2DM group. There was no statistical association between rs11054731 and rs12823243 locus polymorphism and T2DM susceptibility before covariate adjustment (P0.05). After adjusting sex, age, smoking, alcohol consumption, high fat diet, vegetable and fruit intake, physical activity, family history of T2DM and BMI, the risk of T2DM for rs11054731 locus was 1.54 (1.01-2.36) .3. Haplotype analysis showed that there was no difference in frequency distribution between T2DM group and non-T2DM group, and there was no significant correlation between Rs11054731 and GA,AT,AA,GT in T2DM susceptibility (P0.05). No association between genetic risk score and T2DM was found. 4. 4. In the three models, compared with only environmental factors, the net re-classification index was 3.06 and 0.79, respectively, but there was no significant difference in the T2DM discriminant efficacy (P0.05) .rs11054731 and rs12823243 locus and environmental factors. No interaction was found in the susceptibility of T2DM. Conclusion the AG genotype at rs11054731 locus of LRP6 gene can increase the risk of T2DM. There is no association between haplotype and genetic risk score of two loci of LRP6 gene and susceptibility to T2DM. LRP6 gene and environmental factors are not found in T2DM. No interaction was found in the occurrence of the.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R587.1

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