| Objective Type 2 diabetes mellitus（T2DM）has become a worldwide public health problem.It is a complex chronic disease caused by genetic,environmental factors and gene-environment interactions,but the specific pathogenesis of T2DM is still unclear.The results of studies on factors affecting T2DM are still not fully consistent,and the association results of some genes and gene-environment interactions with T2DM are less reported in the Chinese population.In this study,we conducted a case-control study of T2DM based on the community population of Nanning,Guangxi,collected epidemiological data and laboratory test indicators from the research subjects,and analyzed the association between environmental factors,gene and T2DM,and explored possible gene-environment interaction in the risk of T2DM,in order to provide a basis for research on the mechanism of T2DM incident and development,early identification of high-risk population of T2DM,early individualization of high-risk population,precise treatment and prognosis.Methods Part Ⅰ:A case-control study based on community population in Nanning,Guangxi Zhuang Autonomous Region,with 1747 study subjects（968controls and 779 patients with T2DM）finally included according to inclusion and exclusion criteria.Investigators conducted epidemiological surveys,physical examinations,and collected blood samples from the study subjects for follow-up laboratory tests and backup.Exploratory factor analysis was used to extract dietary patterns,and Logistic regression was used to analyze the association of environmental factors with T2DM risk and covariance analysis for association of dietary patterns with T2DM related metabolic traits.Part Ⅱ:DNA was extracted from the first part of the study subjects and we screen out the relevant genes and their single nucleotide polymorphism（SNP）on the NAD+/SIRT1 metabolic pathway,including SIRT1（rs4746720,rs7896005,rs2273773）,NAMPT（rs2058540,rs17152828）,NNMT（rs1941404）,and AOX1（rs55754655）,were genotyped using the SNPscanTM method.Logistic regression was used to analyze the association between SNP,a direct logistic regression genetic risk score（DL-GRS）and T2DM risk;SHEsis and SNPStats online platform used to analyze haplotype of SIRT1 and NAMPT,generalized multifactor dimensionality reduction（GMDR）for association between gene-gene interactions and T2DM risk;covariance analysis for association of gene polymorphisms,DL-GRS and T2DM-related metabolic traits;and expression quantitative trait locus（e QTL）was used to analyze gene m RNA expression in whole blood,liver,skeletal muscle and pancreas.Part Ⅲ:Logistic regression was used to analyze possible joint effect,multiplicative gene-environment interactions in T2DM risk,and relative excess risk due to interaction（RERI）,attributable proportion due to interaction（AP）and synergy index（S）were used to evaluate possible additive gene-environment interactions in T2DM risk,and GMDR was used to analyze possible higher order gene-environment interactions in T2DM risk.Results Part Ⅰ:（1）The proportion of overweight/obesity,SBP,DBP,FBG,2h PG,Hb A1c,FINS,HOMA-IR,TC,TG,LDL-c levels were higher in the T2DM group than in the control group,while HOMA-βand HDL-c levels were lower than in the control group（all P<0.05）.（2）Logistic regression results showed that smoking（OR=1.561,95%CI:1.034-2.359）,overweight/obesity（OR=1.306,95%CI:1.064-1.604）,high SBP levels（OR=1.158,95%CI:1.088-1.305）,and high TG levels（OR=1.302,95%CI:1.122-1.510）were risk factors for increased risk of T2DM.（3）The results of exploratory factor analysis showed that the southern traditional dietary pattern dominated by vegetable and fruit intake was associated with the reduction of T2DM risk,SBP,Hb A1c,TC,TG,and LDL-c levels（all P<0.05）.Part Ⅱ:（1）After adjusting for sex,age,smoking,drinking,physical activity（PA）and BMI,the results showed that the SIRT1 gene rs7896005 had a 34.2%increased risk of T2DM in individuals carrying the AG genotype compared to those carrying the AA genotype in a co-dominant model（OR=1.342,95%CI:1.077-1.673,P=0.009）;in the dominant model,individuals carrying the AG or GG genotype had a 31.8%increased risk of T2DM compared to individuals carrying the AA gene（OR=1.318,95%CI:1.063-1.634,P=0.012）.NAMPT gene rs17152828 in the co-dominant model,individuals carrying the CT genotype had a 29.0%increased risk of T2DM compared to individuals carrying the CC gene（OR=1.290,95%CI:1.024-1.624,P=0.030）;in the dominant model,individuals carrying the CT or TT In the dominant model,individuals carrying the CT or TT genotype had a 28.8%increased risk of T2DM compared to those carrying the CC genotype（OR=1.288,95%CI:1.036-1.601,P=0.022）.The risk of T2DM was significantly higher in the Q3 and Q4 groups of DL-GRS than in the Q1 group（OR=1.345,95%CI:1.026-1.762,P=0.032;OR=1.432,95%CI:1.093-1.877,P=0.009）.（3）The results of the respective haplotype of three loci of SIRT1 gene and two loci of NAMPT gene showed that no association was found between the constitutive haplotypes and T2DM risk（all P>0.05）.（4）The results of GMDR analysis showed that no gene-gene interaction was found to be associated with T2DM risk（all P>0.05）.（5）Individuals carrying AG or GG genotype in SIRT1gene rs7896005 had higher FBG,2h PG,and Hb A1c levels compared with those carrying AA genotype（all P<0.05）.（6）The results of e QTL analysis showed,the G allele of SIRT1 gene rs7896005 was associated with SIRT1 gene low expression levels in whole blood,liver and pancreas(P=4.23×10-33,P=1.11×10-2,P=1.82×10-4),and the C allele of rs2373773 was associated with SIRT1 gene high expression levels in skeletal muscle(P=6.5×10-5);the C allele of NAMPT gene rs2058540 was associated with NAMPT gene high expression levels in whole blood and pancreas(P=4.58×10-2,P=3.84×10-2),and the T allele of rs17152828was associated with NAMPT gene low expression levels in skeletal muscle and pancreas(P=2.74×10-2,P=9.57×10-4).Part Ⅲ:（1）The results of the multiplicative interaction showed that there was a joint effect of SIRT1 gene rs4746720 dominant model and lifestyle in increasing the risk of T2DM（OR=1.625,95%CI:1.216-2.172）and a positive multiplicative interaction(ORmulti=1.669,95%CI:1.090-2.172).The rs7896005dominant model and diet in increasing the risk of T2DM with a joint effect（OR=1.511,95%CI:1.111-2.055）and a negative multiplicative interaction(ORmulti=0.546,95%CI:0.353-0.843).The rs2273773 dominant model and BMI in increasing the risk of T2DM with a joint effect（OR=1.580,95%CI:1.212-2.061）and,and the rs2273773 dominant model and lifestyle with a negative multiplicative interaction(ORmulti=0.623,95%CI:0.412-0.942).The rs2058540dominant model of NAMPT gene and BMI in increasing the risk of T2DM with a joint effect（OR=1.614,95%CI:1.221-2.132）and a negative multiplicative interaction(ORmulti=0.614,95%CI:0.412-0.913).The rs17152828 dominant model of NAMPT gene and lifestyle in increasing the risk of T2DM with a joint effect（OR=1.885,95%CI:1.393-2.552）and a positive multiplicative interaction(ORmulti=1.719,95%CI:1.086-2.784).The DL-GRS and lifestyle in increasing the risk of T2DM with a joint effect（OR=2.322,95%CI:1.720-3.135）and a positive multiplicative interaction(ORmulti=1.552,95%CI:1.023-2.353).（2）The results of additive interactions in dominant model showed that rs4746720 of SIRT1 gene has a synergistic additive interaction with lifestyle（RERI=0.665,95%CI:0.177-1.153）;dominant model of rs7896005 may have an antagonistic additive interaction with diet（RERI=-0.842,95%CI:-1.159--0.093）and possible synergistic additive interaction with smoking（AP=0.496,95%CI:0.063-0.929）in T2DM risk;rs2273773 may have an antagonistic additive interaction with lifestyle（RERI=-0.685,95%CI:-1.331--0.038）in T2DM risk.The rs2058540dominant model of NAMPT gene have an antagonistic additive interaction with BMI（RERI=-0.791,95%CI:-1.511--0.071）;rs17152828 may have a synergistic additive interaction with BMI,diet and lifestyle（RERI=0.615,95%CI:0.153-1.077;RERI=0.427,95%CI:0.034-0.821;RERI=0.789,95%CI:0.257-1.323）in T2DM risk.DL-GRS had a synergistic additive interaction with lifestyle（RERI=0.875,95%CI:0.193-1.558）in T2DM risk.（3）The GMDR results showed that the optimal model of two-factor interaction was the BMI and rs17152828（P=0.011）.Conclusions（1）Smoking,overweight/obesity,high SBP,and high TG levels were risk factors for increased risk of T2DM.The southern traditional dietary pattern dominated by vegetable and fruit intake is associated with lower T2DM risk,SBP,Hb A1c,TC,TG,LDL-c levels.（2）SIRT1 gene rs7896005,NAMPT gene rs17152828,and high DL-GRS were associated with increased risk of T2DM;SIRT1 gene rs7896005 was associated with SIRT1 gene low expression levels in whole blood,liver and pancreas NAMPT gene rs17152828 was associated with NAMPT gene low expression levels in skeletal muscle and pancreas.（3）In the risk of T2DM,SIRT1 gene rs4746720 has a positive multiplicative interaction and a synergistic additive interaction with lifestyle;rs7896005 may has a synergistic additive interaction with smoking,and has a negative multiplicative interaction and an antagonistic additive interaction with diet;rs2273773 has a negative multiplicative interaction with BMI and a possible negative multiplicative interaction and an antagonistic additive interaction with lifestyle.（4）In the risk of T2DM,NAMPT gene rs2058540 have a negative multiplicative interaction and an antagonistic additive interaction with BMI;rs17152828 may have a positive multiplicative interaction and a synergistic additive interaction with lifestyle,had a synergistic additive interaction with BMI and dietary.（5）In the risk of T2DM,DL-GRS have a positive multiplicative interaction and have a negative multiplicative interaction and an antagonistic additive interaction with BMI additive interaction with lifestyle.（6）SIRT1 gene rs7896005 and NAMPT gene rs17152828 can be used as risk loci for early identification of T2DM high-risk population,and can also be used as focus points to explore the mechanism of T2DM and potential therapeutic targets,and provide individualized intervention and treatment for T2DM high-risk population. |
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