Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.
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Authors
Fraszczyk, Eliza
Spijkerman, Annemieke MW
Zhang, Yan
Brandmaier, Stefan
Day, Felix R
Zhou, Li
Wackers, Paul
Dollé, Martijn ET
Bloks, Vincent W
Gào, Xīn
Gieger, Christian
Kooner, Jaspal
Kriebel, Jennifer
Picavet, H Susan J
Rathmann, Wolfgang
Schöttker, Ben
Loh, Marie
Verschuren, WM Monique
van Vliet-Ostaptchouk, Jana V
Chambers, John C
Grallert, Harald
Brenner, Hermann
Luijten, Mirjam
Snieder, Harold
Publication Date
2022-02-15Journal Title
Diabetologia
ISSN
0012-186X
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Fraszczyk, E., Spijkerman, A. M., Zhang, Y., Brandmaier, S., Day, F. R., Zhou, L., Wackers, P., et al. (2022). Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.. Diabetologia https://doi.org/10.1007/s00125-022-05652-2
Abstract
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 HbA1c) 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.
Keywords
Biomarkers, DNA methylation, Epigenetics, Epigenome-wide association studies, Meta-analysis, Prediction, Prospective studies, Type 2 diabetes
Sponsorship
MRC (MC_UU_00006/1)
Medical Research Council (MR/N003284/1)
Cancer Research Uk (None)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/2)
Identifiers
External DOI: https://doi.org/10.1007/s00125-022-05652-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334213
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