The Effects Of MiRNA Processing Genes SNPs And Their Interactions With Environmental Factors On Type 2 Diabetes Mellitus And Vascular Complication

Objective It has been reported that mi RNAs were closely related to type 2 diabetes and its vascular complications because of the important role the mi RNAs play in the regulation of inflammation related genes and pancreatic ? cell.RAN,XPO5,DICER1 and TABP2 are the key processing enzymes in the biosynthesis of mi RNAs,which may affect the expression of the T2 DM and its vascular complications related proteins by regulating the generation of related mi RNAs.However,the relationship between the mi RNA processing genes and T2 DM and its vascular complications is still unknown.Therefore,our study is aimed at investigating the potential association between the genetic polymorphisms of mi RNA processing genes(RAN,XPO5,DICER1 and TARBP2)and the susceptibility of type 2 diabetes mellitus(T2DM)and diabetic vascular complications,as well as further analyze their interaction with environment factors in T2 DM.Methods This is case-control study which contains 743 T2 DM patients and 864 healthy control individuals.Lately,we also set up 3 comparison groups among T2 DM patients: T2 DM with none complications(266 individuals)vs T2 DM with macrovascular complications(108 individuals);T2DM with none complications(266 individuals)vs T2 DM with microvascular complications(266 individuals)and T2 DM with none complications(266 individuals)vs T2 DM with macro-microvascular complications(96 individuals).1.We collected the demographic characteristics(age,BMI and gender etc.),clinical characteristics(triglyceride,high-density lipoprotein,low-density lipoprotein and total cholesterol etc.)and the peripheral blood samples from all the included study population.2.The targeted SNPs of RAN/XPO5/DICER1/TARBP2 were determined through a search on the Hap Map database based on the genotype information from Han Chinese in Beijing,China.Additionally,the genotypes of the targeted SNPs were tested by the matrix assisted laser desorption ionization time of flight mass spectrometry.3.For the continuous variables,the T-test or Manny-Whitney test were used to evaluate differences in the clinical parameters between different comparison groups,otherwise the ?2 test(for categorical variables)would be performed.We conducted logistic regression with co-dominant,dominant and recessive models to calculate the ORs and 95% confidence intervals(CI)for estimating risk.The four selected SNPs identified in the best model of gene-gene interaction models and gene-environment interaction models were performed by MDR(multifactor dimensionality reduction)software.Results 1.Compared with healthy controls,T2 DM patients had larger numbers of male,elder age,higher body mass index(BMI),triglyceride(TG)levels,fasting blood glucose(FBG)levels,GPT(Glutamic-pyruvic,transaminase)levels,serum creatinine levels and blood uric acid levels,but lower high-density lipoprotein(HDL)and(low-density lipoprotein(LDL)levels.Compared with T2 DM patients with none complication,all T2 DM patients with microvascular complications,macrovascular complications and micro-macrovascular complication had elder age,higher prevalence in hypertension and longer duration of T2 DM,but lower GPT levels and estimated glomerular filtration rate(e GFR).Besides,both the T2 DM patients with microvascular complications and macrovascular complications are have higher level of high-density lipoprotein.2.We identified a 36% decreased risk of developing T2 DM for individuals with minor A allele in DICER1 rs13078(OR=0.64,95%CI=0.44-0.92,P=0.014).The individuals with TA or TA+AA genotype in DICER1 rs13078 had 0.58 or 0.68 lower risk of developing type 2 diabetes than individuals with TT genotype(TA: OR=0.62,95%CI=0.41-0.94,P=0.022;TA+AA: OR=0.65,95%CI=0.43-0.98,P=0.040).3.The T2 DM patients with TT+TC genotype in RAN rs14035 had 1.89 times higher risk of developing macrovascular complications compared with patients with CC genotype(OR=1.89,95%CI=1.04-3.45,P=0.037).4.We also identified two three-factor interaction models.One is three-factor(DICER1 rs13078,high-density lipoprotein(HDL)and triglyceride(TG))interaction models for T2 DM.The individuals with all three factors(mutation of rs13078,low HDL and high TG)had 11.42 times higher risk of developing T2 DM compared with the individuals with wild-type of rs13078,normal HDL and normal TG(OR=12.42,95%CI=2.71-57.15,P=0.001).Another one is three-factor(Ran rs14035,hypertension(HP)and duration of T2DM(DOD)interaction models for macrovascular complications of T2 DM.The individuals with all three factors(mutation of rs14035,with hypertension and longer duration of T2DM)had 40.60 times higher risk of developing T2 DM macrovascular complications compared with the T2 DM patients with wild-type of rs14035,none hypertension and shorter duration of T2DM(OR=41.60,95%CI=11.75-147.35,P<0.001).Conclusion Our study provides the new evidences that both the SNPs in the mi RNA processing genes,DICER1 and RAN gene,and their interactions with certain environment factors might contribute to the risk of T2 DM and its vascular complications in the southern Chinese population.