biostudies-literatureHuo WNanshan District Science and Technology Program Key Project of ShenzhenPostdoctoral Research Foundation of ChinaGuangdong Basic and Applied Basic Research FoundationBasic and Applied Basic Research Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaKey R & D and promotion projects in Henan ProvinceShenzhen Science and Technology Programe13512https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940902biostudies-literatureUnknown16(3)<h4>Aims</h4>To investigate the association of methylation risk score (MRS) and its interactions with environmental factors with type 2 diabetes mellitus (T2DM) risk.<h4>Methods</h4>We conducted a nested case-control study with 241 onset cases and 241 matched controls. Conditional logistic regression models were employed to identify risk CpG sites. Simple and weighted MRSs were constructed based on the methylation levels of ATP-binding cassette G1 gene, fat mass and obesity associated gene, potassium voltage-gated channel member 1 gene, and thioredoxin-interacting protein gene previously associated with T2DM to estimate the association of MRS with T2DM risk. Stratified analyses were used to investigate interactions between MRS and environmental factors.<h4>Results</h4>A total of 10 CpG loci were identified from the aforementioned genes to calculate MRS. After controlling for potential confounding factors, taking tertile 1 as reference, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM of tertile 3 was 2.39 (1.36-4.20) for simple MRS and 2.59 (1.45-4.63) for weighted MRS. With per SD score increment in MRS, the OR (95% CI) was 1.66 (1.29-2.14) and 1.60 (1.24-2.08) for simple and weighted MRSs, respectively. J-curved associations were observed between both simple and weighted MRSs and T2DM risks. Additionally, multiplication interactions for smoking and hypertension with simple MRS on the risk of T2DM were found, similarly for smoking and obesity with weighted MRS on the risk of T2DM (all P_interaction  < .05).<h4>Conclusion</h4>Elevated simple and weighted MRSs were associated with increased risk of T2DM. Environmental risk factors may influence the association between MRS and T2DM.Journal of diabetesAssociation of methylation risk score with incident type 2 diabetes mellitus: A nested case-control study.PMC109409028227370781973152NS20220092321023110178230422882073646821039402021A1515012503JCYJ202103240936120322021M692903JCYJ202208180958180402022A1515010503Liu JZhang JFu XFeng YYuan LZhang MZhao YWang LKe YWang MZhang WSun LLi XHu FHu DHuo WLi THuang ZHu HGao YChen YWu YfalseAssociation of methylation risk score with incident type 2 diabetes mellitus: A nested case-control study.<h4>Aims</h4>To investigate the association of methylation risk score (MRS) and its interactions with environmental factors with type 2 diabetes mellitus (T2DM) risk.<h4>Methods</h4>We conducted a nested case-control study with 241 onset cases and 241 matched controls. Conditional logistic regression models were employed to identify risk CpG sites. Simple and weighted MRSs were constructed based on the methylation levels of ATP-binding cassette G1 gene, fat mass and obesity associated gene, potassium voltage-gated channel member 1 gene, and thioredoxin-interacting protein gene previously associated with T2DM to estimate the association of MRS with T2DM risk. Stratified analyses were used to investigate interactions between MRS and environmental factors.<h4>Results</h4>A total of 10 CpG loci were identified from the aforementioned genes to calculate MRS. After controlling for potential confounding factors, taking tertile 1 as reference, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM of tertile 3 was 2.39 (1.36-4.20) for simple MRS and 2.59 (1.45-4.63) for weighted MRS. With per SD score increment in MRS, the OR (95% CI) was 1.66 (1.29-2.14) and 1.60 (1.24-2.08) for simple and weighted MRSs, respectively. J-curved associations were observed between both simple and weighted MRSs and T2DM risks. Additionally, multiplication interactions for smoking and hypertension with simple MRS on the risk of T2DM were found, similarly for smoking and obesity with weighted MRS on the risk of T2DM (all P_interaction  < .05).<h4>Conclusion</h4>Elevated simple and weighted MRSs were associated with increased risk of T2DM. Environmental risk factors may influence the association between MRS and T2DM.2024-01-01T00:00:00Z2024 Mar2026-06-26T03:10:35.966Z2026-06-26T03:08:01.884ZS-EPMC109409023806291310.1111/1753-0407.13512