Association Of The Polymorphisms In TLR3,TRIF And TRAF3 Genes,interactions Between Polymorphisms And Environmental Factors On The Risk Of Type 2 Diabetes And Vascular Complications

ObjectiveTLR3,TRIF and TRAF3 pathway has been reported to be implicated in Type 2 diabetes mellitus(T2DM)and its vascular complications.However,the role of gene polymorphism of TLR3,TRIF and TRAF3 is still unclear.Our study aimed to explore the association between TLR3,TRIF and TRAF3 gene polymorphism and T2DM and its vascular complications,and the role of gene-gene and gene-environment interactions on the risk of T2DM and its vascular complications.Methods1.A case-control study was performed,with 552 T2DM patients and 552 healthy control group.We set up three comparision groups among T2DM patients:T2DM with microvascular complications group(221 patients)vs.T2DM group without complication(128 patients);T2DM with macrovascular complications group(63 patients)vs.T2DM group without complication(128 patients);T2DM with both microvascular and macrovascular complications group(71patients)vs.T2DM group without complication(128 patients).2.We collected demographic information(such as age,sex,education,weight,height),biochemical tests(such as TC,TG,HDL,LDL)and the blood sample of the study population.3.SNPs in TLR3,TRIF and TRAF3 genes were screened from the Hapmap database and the genotypes were tested by the matrix assisted laser desorption ionization time of flight mass spectrometry.4.Difference in demographic information and biochemical tests between case and control were compared using student-t test(for continuous data)and?~2 test(for categorical data).The association between TLR3,TRIF and TRAF3 SNPs and T2DM and its vascular complications was cacultaed by conditional or unconditional logistic regression.SHEsis was used to examine the haplotype frequencies and their effects on T2DM and its vascular complications.MDR was used to identify the best gene-gene and gene-environmental interactions model.Results1.Compared with healthy controls,T2DM patients had higher body mass index(BMI),triglyceride(TG)levels but lower high-density lipoprotein(HDL)and low-density lipoprotein(LDL)levels.Compared with T2DM patients without any complication,T2DM patients with macrovascular complications had the older age,T2DM patients with both microvascular and macrovascular complications had the older age and higher HbA1c.2.Eight single nucleotide polymorphisms(SNPs)were genotyped in our study.A significantly higher T allele frequency in TRAF3 rs12435483 was observed in T2DM patients compared with health control under the allelic model(T vs.C:OR=1.21;95%CI:1.01-1.44;P=0.036).No significant was found between TLR3 and TRAF3 SNPs with the susceptibility of T2DM after adjusting BMI,TG,HDL and LDL.The GA genotype and GA+AA genotype of TRAF3 rs12147254 were identified as risk factors for T2DM macrovascular complications(GA vs.GG:OR=2.79,95%CI:1.09-7.13,P=0.032;GA+AA vs.GG:OR=2.55,95%CI:1.03–6.29,P=0.043,respectively)after adjusting age.3.In haplotype analysis,compared with the haplotype CTGC,individuals with the GTGT haplotype in TRAF3 gene have the lower risk of developing T2DM(OR=0.34,95%CI=0.13-0.86,P=0.018).4.Two-factor(TRAF3 rs12435483 and LDL)and three-factor(TRAF3 rs12435483,BMI and HDL)interactions were found to be associated with the risk of T2DM.We found that individuals with all three risk factor(carrying TT+CT genotypes in TRAF3 rs12435483,HDL<1.04 mmol/L and BMI?24kg/m~2)have an increased risk of developing T2DM compared with the reference group(carrying CC genotye in TRAF3 rs12435483,HDL?1.04 mmol/L and BMI<24kg/m~2)(OR=25.32,95%CI:13.24-48.42,P<0.001).ConclusionThe SNPs in TRAF3 genes and its interaction with some fat metabolism environmental factors might contribute to the suspectibility of T2DM and its vascular complications in the south Han Chinese population.