Noro, FabriziaSantonastaso, FedericaMarotta, AnnalisaBonaccio, MarialauraOrlandi, SabatinoTirozzi, AlfonsinaCostanzo, SimonaDe Curtis, AmaliaGianfagna, FrancescoDi Castelnuovo, AugustoBrighenti, FurioCerletti, ChiaraDonati, Maria Benedettade Gaetano, GiovanniIacoviello, LiciaGialluisi, AlessandroIzzi, Benedetta2025-01-172025-01-172022-12-28Clin Epigenetics. 2022 Dec 28;14(1):189.https://hdl.handle.net/20.500.12105/26060The enrollment phase of the Moli-sani study was supported by research grants from the Pfzer Foundation (Rome, Italy), the Italian Ministry of University and Research (MIUR, Rome, Italy)–Programma Triennale di Ricerca, Decreto no.1588 and Instrumentation Laboratory, Milan, Italy. This work was also partially funded by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie (grant agreement No 798841 to BI), by the Italian Ministry of Health (GR 2018-12366528 to BI and AG and Ricerca Corrente 2022–2024). Funders had no role in study design; collection, analysis or interpretation of data, the writing of the manuscript or the decision to submit the article for publication.High dietary glycaemic index (GI) and load (GL) have been associated with increased risk of various cardiometabolic conditions. Among the molecular potential mechanisms underlying this relationship, DNA methylation has been studied, but a direct link between high GI and/or GL of diet and global DNA methylation levels has not been proved yet. We analyzed the associations between GI and GL and global DNA methylation patterns within an Italian population. Genomic DNA methylation (5mC) and hydroxymethylation (5hmC) levels were measured in 1080 buffy coat samples from participants of the Moli-sani study (mean(SD) = 54.9(11.5) years; 52% women) via ELISA. A 188-item Food Frequency Questionnaire was used to assess food intake and dietary GI and GL for each participant were calculated. Multiple linear regressions were used to investigate the associations between dietary GI and GL and global 5mC and 5hmC levels, as well as the proportion of effect explained by metabolic and inflammatory markers. We found negative associations of GI with both 5mC (β (SE) = - 0.073 (0.027), p = 0.007) and 5hmC (- 0.084 (0.030), p = 0.006), and of GL with 5mC (- 0.14 (0.060), p = 0.014). Circulating biomarkers did not explain the above-mentioned associations. Gender interaction analyses revealed a significant association of the gender-x-GL interaction with 5mC levels, with men showing an inverse association three times as negative as in women (interaction β (SE) = - 0.16 (0.06), p = 0.005). Our findings suggest that global DNA methylation and hydroxymethylation patterns represent a biomarker of carbohydrate intake. Based on the differential association of GL with 5mC between men and women, further gender-based separate approaches are warranted.engVoRhttp://creativecommons.org/licenses/by/4.0/Glycaemic indexGlycaemic loadHydroxymethylationMetabolic disordersMethylationAttribution 4.0 International36578055141189Clinical Epigeneticsopen access