Association Of Interactions Between NLRP3 Polymorphisms And Environmental Factors On The Risk Of Type 2 Diabetes And Vascular Complications

Objective NLRP3 inflammsome has been reported to be associated with Type 2 diabetes mellitus(T2DM)and its vascular complications;However,the role of genetic variations of NLRP3 is still unclear.Our study aimed to decipher the relationship between SNPs of NLRP3 and T2 DM and its vascular complications,and interactions of gene-gene,gene-environment on the risk of T2 DM.Methods 1.We used case-control study design and set four comparision groups: T2 DM group vs.healthy group;simple T2 DM group vs.microvascular lesion group;simple T2 DM group vs.macrovascular lesion group;simple T2 DM group vs.both microvascular and macrovascular lesion group.744 T2 DM patients,530 healthy people,304 single T2 DM patients,260 patients with microvascular lesion,98 patients with macrovascular lesion and 82 patients with patients with microvascular and macrovascualr lesion were included.2.Demographic data(sex,age,height,weight,etc.),clinical biochemical parameters(TC,LDL-C,HDL-C,TG,etc.)and blood sample were collected.3.SNPs in NLRP3 were screened and genotypes were tested.SNPs,which conformed to Hardy-Weinberg equilibrium were then analyzed.4.T test was used to analyze continuous data andχ2 test was used to analyze categorical data.Logistic regression was used to analyze the relationship between NLRP3 and T2 DM and vascular complications.Haploview software was used in haplotype analysis.GMDR,Logistic regression models and crossover models were used to analyze gene-gene and gene-environment interactions.Results 1.BMI and TG index in T2 DM group were significantly higher than healthy group,and LDL-C and HDL-C index were significantly lower than healthy group;age in three groups with vascular lesion was significantly older than single T2 DM group;LDL-C in macrovascular lesion group was significantly lower than single T2 DM group.2.We selected 13 SNPs in NLRP3 gene(rs10157379,rs10159239,rs10754557,rs10925025,rs10925026,rs12060377,rs12130711,rs1539019,rs3738447,rs3806265,rs3806268,rs4612666,rs7525979).No significant association was found between NLRP3 with T2 DM and macrovascular complication.After adjusting age and LDL-C,people with rs3806265 TC had lower risk of T2 DM than people with rs3806265 TT(OR = 0.64,95%CI: 0.43-0.96,P = 0.030).Significant associations were found between rs10157379,rs10925025,rs10925026,rs1539019 and patients with both microvascular and macrovascular complications.Under co-dominant model,people with rs10157379 TC or CC had lower risk of both microvascular and macrovascular complications than people with rs10157379 TT(OR = 0.51,95%CI: 0.29-0.90,P = 0.020;OR = 0.44,95%CI: 0.19-0.99,P = 0.047);people with rs10925025 AG had lower risk of both microvascular and macrovascular complications than people with rs10925025 GG(OR = 0.52,95%CI: 0.29-0.92,P = 0.026);people with rs10925026 CA or CC had lower risk of both microvascular and macrovascular complications than people with rs10925026 AA(OR = 0.54,95%CI: 0.30-0.95,P = 0.032;OR = 0.41,95%CI: 0.18-0.95,P = 0.038);people with rs1539019 CA or AA had lower risk of both microvascular and macrovascular complications than people with rs1539019 CC(OR = 0.50,95%CI: 0.28-0.88,P = 0.016;OR = 0.40,95%CI: 0.17-0.92,P = 0.031).Under dominant model,people with rs10157379 CC+TC had lower risk of both microvascular and macrovascular complications than people with rs10157379 TT(OR = 0.49,95%CI: 0.29-0.83,P = 0.008);people with rs10925025 AA+AG had lower risk of both microvascular and macrovascular complications than people with rs10925025 GG(OR = 0.50,95%CI: 0.29-0.86,P = 0.011);people with rs10925026 CC+CA had lower risk of both microvascular and macrovascular complications than people with rs10925026 AA(OR = 0.50,95%CI: 0.29-0.85,P = 0.011);people with rs1539019 AA+CA had lower risk of both microvascular and macrovascular complications than people with rs1539019 CC(OR = 0.47,95%CI: 0.28-0.80,P = 0.005).Under allele model,people with rs10157379 C had lower risk of both microvascular and macrovascular complications than people with rs10157379 T;people with rs10157379 C had lower risk of both microvascular and macrovascular complications than people with rs10157379 T(OR = 0.66,95%CI: 0.46-0.95,P = 0.027);people with rs10925025 A had lower risk of both microvascular and macrovascular complications than people with rs10925025 G(OR = 0.67,95%CI: 0.46-0.97,P = 0.031);people with rs10925026 C had lower risk of both microvascular and macrovascular complications than people with rs10925026 A(OR = 0.63,95%CI: 0.44-0.92,P = 0.016);people with rs1539019 A had lower risk of both microvascular and macrovascular complications than people with rs1539019 C(OR = 0.61,95%CI: 0.42-0.89,P = 0.011).3.In hyplotype analysis,T2 DM patients with rs1539019-rs10925025-rs10925026-s10157379 AACC had lower risk of both microvascular and macrovascular comlications than T2 DM patients with CGAT(OR = 0.61,95% CI: 0.41-0.90,P = 0.014).4.The interactions of rs3738447*BMI*HDL-C and rs4612666*BMI*HDL-C*TG were significantly associated with T2 DM.The interactions of rs1539019*rs4612666 and rs1539019*LDL-C were negatively associated with T2 DM with both microvascular and macrovascular comlications.Conclusion Several SNPs in NLRP3 may influence the risk of T2 DM and its vascular complications,which should be confirmed in further study.