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@ARTICLE{Fraszczyk:178958,
      author       = {E. Fraszczyk and A. M. W. Spijkerman and Y. Zhang$^*$ and
                      S. Brandmaier and F. R. Day and L. Zhou and P. Wackers and
                      M. E. T. Dollé and V. W. Bloks and X. Gào$^*$ and C.
                      Gieger and J. Kooner and J. Kriebel and H. S. J. Picavet and
                      W. Rathmann and B. Schöttker$^*$ and M. Loh and W. M. M.
                      Verschuren and J. V. van Vliet-Ostaptchouk and N. J. Wareham
                      and J. C. Chambers and K. K. Ong and H. Grallert and H.
                      Brenner$^*$ and M. Luijten and H. Snieder},
      title        = {{E}pigenome-wide association study of incident type 2
                      diabetes: a meta-analysis of five prospective {E}uropean
                      cohorts.},
      journal      = {Diabetologia},
      volume       = {65},
      number       = {5},
      issn         = {0012-186X},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2022-00374},
      pages        = {763-776},
      year         = {2022},
      note         = {2022 May;65(5):763-776},
      abstract     = {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.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).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.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 (Other) / DNA methylation (Other) / Epigenetics
                      (Other) / Epigenome-wide association studies (Other) /
                      Meta-analysis (Other) / Prediction (Other) / Prospective
                      studies (Other) / Type 2 diabetes (Other)},
      cin          = {C070},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35169870},
      doi          = {10.1007/s00125-022-05652-2},
      url          = {https://inrepo02.dkfz.de/record/178958},
}