Association Of GCKR Polymorphisms With Type 2 Diabetes Mellitus In Han Population

ObjectivesThe purposes of this study are to evaluate the effect between single-nucleotide polymorphisms(SNPs)of the GCKR gene and the risk of type 2 diabetes mellitus(T2DM),and to illustrate the interactions between environmental risk factors and GCKR variants on the risk of T2 DM.MethodsSubjects of this prospective nested case-control study were selected from the “the Rural Chinese Cohort Study”.A total of 538 cases of newly developed T2 DM during the follow-up period were selected as the case group.According to the similar conditions of age(within 2 years),gender,marital status,and village,each case was matched individually with a non-T2 DM control randomly.Three SNPs in the GCKR genes including rs780094,rs2293572 and rs1260326 were genotyped using an SNPscan? kit.Multifactor conditional logistic regression models were used to generate odds ratios(ORs)and 95% confidence intervals(CI)for traditional risk factors and GCKR variants for the risk of T2 DM.The association between GCKR gene haplotypes and T2 DM susceptibility was analyzed by R software.Genetic risk score was constructed to analyze its association with T2 DM risk.Using conditional logistic regression model and the additive model proposed by Rothman and Hosmer,respectively,to evaluate the effects of multiplicative and additive interactions between gene loci and environmental factors on T2 DM risk.Classification and regression tree(CART)models were used to evaluate the effect of multifactor interaction between GCKR SNPs and environmental factors on T2 DM risk.Linear regression model was used to analyze the effect of GCKR genetic risk score(GRS)on glucose metabolism related indexes and scrum lipid levels.Results1.At the baseline,there were statistically significant higher levels of the total cholesterol(TC),high-density lipoprotein(HDL-C),triglycerides(TG),and fasting plasma glucose(FPG),body mass index(BMI),waist circumference(WC)and higher proportion of central obesity,general overweight/obesity,dyslipidemia patients and people with family history of diabetes in the T2 DM group compared with the control group.2.Univariate conditional logistic regression showed that higher BMI,WC,TG,TC,FPG levels,and family history of T2 DM,general overweight/obesity,central obesity and dyslipidemia all increased the risk of T2DM(P<0.05),but HDL-C level decreased the risk of T2DM(P<0.05).3.After adjusting for baseline BMI,family history of diabetes and dyslipidemia,for rs780094,compared with those with CC genotype,the risk of T2 DM was decreased among people who carrying the TT genotype in the additive model(OR=0.54,95%CI= 0.31-0.94)(P<0.05).However,there was no statistical association between other SNPs(rs2293572 and rs1260326)and the risk of T2 DM in each model(P>0.05).4.Haplotypes analysis showed that there was no statistical association between the 6 haplotypes of CCT,TCC,TCT,CCC,CGT TGC and T2 DM risk(P>0.05).No association between genetic risk score and the risk of T2 DM susceptibility was found.5.Multiplicative and additive interaction models showed that there was no interaction between GCKR polymorphisms and environmental factors on T2 DM risk.CART model showed that there was the highest risk among the individuals with central obesity,general overweight/obesity,dyslipidemia and rs2293572 variants comparing with those without central obesity and dyslipidemia(OR=8.98,95% CI=4.04-19.99).6.The association between GRS of GCKR gene and related indexes of glucose metabolism and scrum lipid levels results in different groups showed that GRS of GCKR gene were positively correlated with baseline levels of TC,TG and HDL-C levels in the total group after adjusting for baseline age,gender and BMI(P<0.05),and GRS were found positively correlated with TC and HDL-C levels(P<0.05)in the control group,in the case group only the TG level was found positively correlated with GRS(P<0.05).However,no association was found between GRS of GCKR gene and baseline FPG,FPG change and HOMA-IR level during follow-up(P>0.05).Conclusions1.The T allele of GCKR rs780094 is associated with decreased risk of T2 DM in Chinese rural Han population.2.The haplotype and genetic risk score of the GCKR gene are not associated with T2 DM susceptibility.3.The risk of T2 DM may be affected by the interaction between rs2293572 variant and a variety of environmental factors(general obesity,central obesity and dyslipidemia).4.GCKR genetic risk score may associate with scrum TG level.