| ObjectivesTo estimate the association between the methylation levels and polymorphisms of Thioredoxin-interacting protein(TXNIP)and the risk of type 2 diabetes mellitus(T2DM),to evaluate the interaction among DNA methylation,polymorphisms and environmental factors on T2 DM risk,and to explore the association between TXNIP methylation,polymorphism and metabolic indicators.MethodsThis nested case-control study included 286 incident T2 DM cases and 286 non-T2 DM controls matched by sex,age,marital status,race,and residence village.The methylation level and genetype of the TXNIP gene were quantitatively detected by the Time of Flight Mass Spectrometry technology.Conditional logistic regression was used to select environmental risk factors of T2 DM and to estimate the association of TXNIP gene methylation levels and genetic polymorphisms with the risk of T2 DM.In addition,interaction among TXNIP methylation,polymorphisms and environmental factors were explored by classification and regression tree(CART).We further evaluated the effect of interaction on T2 DM susceptibility by conditional logistic regression.In the control group,we used median regression to analyze the association between methylation levels,genetic polymorphisms and metabolic indicators,and logistic regression to analyze the association between genetic polymorphisms and metabolic indicators.Results1.There were significant differences in the distribution of the levels of baseline body mass index(BMI),systolic blood pressure,diastolic blood pressure,fasting blood glucose,triglyceride(TG)and high-density lipoprotein cholesterol(HDL-C),and the proportions of obesity,hypertriglyceridemia(HTG),low HDL-C,hypertension and family history of T2 DM between T2 DM and controls(P<0.05).2.Univariate conditional logistic regression analysis showed that individuals with obesity,HTG and hypertension had an increased risk of T2 DM incidence by 119%(Odd ratio [OR] 95% Confidence interval [CI],2.19 [1.43-3.35]),139%(2.39 [1.51-3.77]),88%(1.88 [1.28-2.75]),respectively.3.The methylation levels of TXNIP gene in the T2 DM group were significantly lower than that in the control group(P<0.05).After adjusted for the potential confounders,conditional logistic regression analysis showed that hypomethylation of CpG1,CpG3 and CpG4 significantly increased the risk of T2DM(OR[95%CI]: CpG1,1.18 [1.00-1.39];CpG3,1.32 [1.04-1.69];CpG4,1.20 [1.01-1.42]).4.Under the dominant,co-dominant and recessive genetic model,conditional logistic regression analysis showed that the rs7211 and rs7212 polymorphisms were not associated with T2DM(P>0.05).5.CART model presented the interaction of obesity,HTG and TXNIP hypomethylation.Compared to individuals with high levels of TXNIP methylation and normal levels of BMI and triglyceride,people exposed to HTG,obesity and hypomethylation of TXNIP gene had a significantly increased risk of T2 DM incidence.6.Among control group,the methylation levels of CpG2,CpG3 and CpG4 were significantly lower in individuals with rs7211 or rs7212 mutation type than who with wild homozygote(P<0.05).Compared to individuals with normal TG level,patients with HTG had higher methylation levels of CpG3 and CpG4(P<0.05).Individuals with rs7212 mutation showed a higher risk of obesity,compared to those with wild homozygote(P=0.044).ConclusionsThis study found that the hypomethylation of TXNIP gene increased the risk of T2 DM in Chinese population.However,there was no significant association between TXNIP gene polymorphisms and T2 DM risk.Moreover,the interaction of TXNIP gene hypomethylation,obesity and HTG may play important role in development of T2 DM.In addition,the methylation level of TXNIP gene was related to its variants and TG level,and its variant was closely related to obesity. |
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