Details

Autor(en) / Beteiligte

• Fraszczyk, Eliza
• Spijkerman, Annemieke M. W.
• Zhang, Yan
• Brandmaier, Stefan
• Day, Felix R.
• Zhou, Li
• Wackers, Paul
• Dollé, Martijn E. T.
• Bloks, Vincent W.
• Gào, Xīn
• Gieger, Christian
• Kooner, Jaspal
• Kriebel, Jennifer
• Picavet, H. Susan J.
• Rathmann, Wolfgang
• Schöttker, Ben
• Loh, Marie
• Verschuren, W. M. Monique
• van Vliet-Ostaptchouk, Jana V.
• Wareham, Nicholas J.
• Chambers, John C.
• Ong, Ken K.
• Grallert, Harald
• Brenner, Hermann
• Luijten, Mirjam
• Snieder, Harold

Titel

Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts

Ist Teil von

• Diabetologia, 2022-05, Vol.65 (5), p.763-776

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 × 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 HbA 1c ) 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. Graphical abstract