Journal
DIABETOLOGIA
Volume 65, Issue 5, Pages 763-776Publisher
SPRINGER
DOI: 10.1007/s00125-022-05652-2
Keywords
Biomarkers; DNA methylation; Epigenetics; Epigenome-wide association studies; Meta-analysis; Prediction; Prospective studies; Type 2 diabetes
Categories
Funding
- Ministry of Health, Welfare and Sport of the Netherlands
- National Institute for Public Health and the Environment [S/132005]
- Biobanking and Biomolecular Resources Research Infrastructure-NL [CP2011-27]
- Baden-Wurttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany)
- Federal Ministry of Education and Research (Berlin, Germany)
- Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany)
- Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- BMBF
- Ministry of Culture and Science of the State North Rhine-Westphalia (Dusseldorf, Germany)
- Deutsche Forschungsgemeinschaft [RA 459/3-1]
- Munich Center of Health Sciences (MC-Health), LudwigMaximilians-Universitat, LMUinnovativ
- Medical Research Council (MRC) [G9502233]
- Cancer Research UK [C864/A8257]
- MRC Cambridge Initiative in Metabolomic Science [MR/l00002/1]
- MRC programme awards [MC_UU_ 12015/1, MC_UU_12015/2]
- National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust
- NIHR Official Development Assistance (ODA) [16/136/68]
- European Union [279143, 643774]
- Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award [NMRC/STaR/0028/2017]
- H2020 Societal Challenges Programme [643774] Funding Source: H2020 Societal Challenges Programme
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This study aimed to identify predictive methylation markers for incident type 2 diabetes by combining results from five European cohorts. The results showed an association between DNA methylation levels and incident type 2 diabetes, which was consistent across different ethnicities. Furthermore, BMI partly explained this association.
Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. Methods We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). Results The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 x 10(-7)). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbAlc) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. Conclusions/interpretation By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.
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