| ObjectivesTo estimate the associations between methylation of ATP-binding cassette G1(ABCG1)gene and its dynamic change and the risk of incident type 2 diabetes mellitus(T2DM),the associations between polymorphisms of ABCG1 gene and the risk of incident T2 DM,and to explore the interactions among ABCG1 gene methylation levels,ABCG1 gene polymorphisms and environmental risk factors,so as to provide epidemiological evidence for the prevention and control of T2 DM.MethodsWe conducted a prospective nested case-control study based on the Rural Chinese Cohort Study.Patients newly diagnosed with T2 DM during the follow-up were selected as the case group,controls were 1:1 matched according to age,sex,village of residence,race and marital status and selected from the subjects who did not develop T2 DM during the follow-up.If more than one control met the requirements,the control is determined by random sampling.A total of 283 pairs of T2 DM cases and controls were eventually included.Methylation levels in the promoter region of ABCG1 gene at baseline and follow up,and ABCG1 gene polymorphisms were detected by the time-of-flight mass spectrometry.The dynamic change in DNA methylation level was calculated as methylation level at follow-up minus the level at baseline examination.Conditional logistic regression models were used to estimate incident T2 DM risk according to ABCG1 gene methylation level at baseline and its dynamic change during follow-up,and ABCG1 gene polymorphisms.The odds ratio(OR)and 95% confidence interval(CI)were reported.Classification and regression tree(CART)model was used to explore the multi-factor interaction between ABCG1 gene and environmental factors,and potential pathways influencing the incidence of T2 DM were screened out.Conditional logistic regression model was used to further analyze the risk of T2 DM associated with different pathways.Unconditional logistic regression was used to analyze the associations between ABCG1 gene methylation level,ABCG1 gene polymorphisms and related metabolic indicators affecting the risk of T2 DM.Results1.A total of 283 case and control pairs were included in this study.At baseline,the levels of body mass index,systolic blood pressure,diastolic blood pressure,fasting plasma glucose,triglyceride and high-density lipoprotein cholesterol,and the proportions of obesity,dyslipidemia and history of hypertension were significantly different between the two groups(P > 0.05).2.Hypermethylation of the ABCG1 loci CpG13＿14 was associated with increased T2 DM risk.T2 DM risk was increased by 18%(OR = 1.18,95% CI:1.04-1.35)with each 1% increase in methylation levels of the ABCG1 loci CpG13＿14in the range of 67% to 79%.3.Methylation change of the ABCG1 locus CpG15 during the 6-year follow-up was associated with increased T2 DM risk.T2 DM risk increased by 80% in the upper tertile group(methylation gain ≥5%)versus lower tertile group(methylation gain<1%)(OR = 1.80,95% CI: 1.01-3.21).4.Under additive,dominant,and recessive genetic models,no association was found between ABCG1 gene polymorphisms(rs8126971,rs2234714,rs2234715,rs57137919,rs1044317,rs4148140,rs2839483,rs7283700,rs1893590,and rs225374)with T2 DM risk(P > 0.05).5.CART model showed a multi-factor interaction between obesity,history of hypertension,dyslipidemia,and the methylation level of the ABCG1 locus CpG6＿8.Among those without obesity and dyslipidemia,participants with the methylation level of the ABCG1 locus CpG6＿8 > 92% had a 1.67-fold increased risk of T2 DM compared to CpG6＿8 ≤ 92%(OR = 2.67,95% CI: 1.25-5.69).6.Within the control group,hypermethylation of the ABCG1 loci CpG6＿8 and CpG15 was associated with increased obesity risk(CpG6＿8: OR = 1.09,95% CI:1.01-1.18;CpG15: OR = 1.16,95% CI: 1.06-1.27);Hypermethylation of the ABCG1 locus CpG12 was associated with increased dyslipidemia risk(OR = 1.10,95% CI:1.01-1.22);For rs2234714,compared with those carrying the GA and GG genotype,those who carrying the AA genotype had a 1.07-fold increased obesity risk(OR =2.07,95% CI: 1.03-4.15);For rs1893590,compared with those carrying the AA genotype,those who carrying the CC genotype had a 1.51-fold increased obesity risk(OR = 2.51,95% CI: 1.04-6.05);ConclusionsIn our study,methylation levels of the ABCG1 loci CpG13＿14 and the increase of the dynamic change in the methylation levels of the ABCG1 locus CpG15 could increase the risk of T2 DM.The methylation of ABCG1 gene may play a role in the development of T2 DM,this study provides a scientific basis for clarifying the epigenetic background of T2 DM.Meanwhile,the interaction between obesity,history of hypertension,dyslipidemia,and the methylation levels of the ABCG1 loci CpG6＿8could influence the progression of T2 DM.There are also associations between ABCG1 gene methylation levels and obesity,ABCG1 gene methylation levels and dyslipidemia,and ABCG1 gene polymorphisms and obesity.The mechanism of such association needs to be further studied to develop a scientific prevention strategy for T2 DM. |
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