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@ARTICLE{Zheng:164050,
      author       = {J.-S. Zheng and J. Luan and E. Sofianopoulou and S. J.
                      Sharp and F. R. Day and F. Imamura and T. E. Gundersen and
                      L. A. Lotta and I. Sluijs and I. D. Stewart and R. L. Shah
                      and Y. T. van der Schouw and E. Wheeler and E. Ardanaz and
                      H. Boeing and M. Dorronsoro and C. C. Dahm and N. Dimou and
                      D. El-Fatouhi and P. W. Franks and G. Fagherazzi and S.
                      Grioni and J. M. Huerta and A. K. Heath and L. Hansen and M.
                      Jenab and P. Jakszyn and R. Kaaks$^*$ and T. Kühn$^*$ and
                      K.-T. Khaw and N. Laouali and G. Masala and P. M. Nilsson
                      and K. Overvad and A. Olsen and S. Panico and J. R. Quirós
                      and O. Rolandsson and M. Rodríguez-Barranco and C.
                      Sacerdote and A. M. W. Spijkerman and T. Y. N. Tong and R.
                      Tumino and K. K. Tsilidis and J. Danesh and E. Riboli and A.
                      S. Butterworth and C. Langenberg and N. G. Forouhi and N. J.
                      Wareham},
      title        = {{T}he association between circulating 25-hydroxyvitamin {D}
                      metabolites and type 2 diabetes in {E}uropean populations:
                      {A} meta-analysis and {M}endelian randomisation analysis.},
      journal      = {PLoS medicine},
      volume       = {17},
      number       = {10},
      issn         = {1549-1676},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DKFZ-2020-02218},
      pages        = {e1003394 -},
      year         = {2020},
      abstract     = {Prior research suggested a differential association of
                      25-hydroxyvitamin D (25(OH)D) metabolites with type 2
                      diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely
                      associated with T2D, but the epimeric form (C3-epi-25(OH)D3)
                      positively associated with T2D. Whether or not these
                      observational associations are causal remains uncertain. We
                      aimed to examine the potential causality of these
                      associations using Mendelian randomisation (MR) analysis.We
                      performed a meta-analysis of genome-wide association studies
                      for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and
                      C3-epi-25(OH)D3 (N = 40,562) in participants of European
                      descent (European Prospective Investigation into Cancer and
                      Nutrition [EPIC]-InterAct study, EPIC-Norfolk study,
                      EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We
                      identified genetic variants for MR analysis to investigate
                      the causal association of the 25(OH)D metabolites with T2D
                      (including 80,983 T2D cases and 842,909 non-cases). We also
                      estimated the observational association of 25(OH)D
                      metabolites with T2D by performing random effects
                      meta-analysis of results from previous studies and results
                      from the EPIC-InterAct study. We identified 10 genetic loci
                      associated with total 25(OH)D, 7 loci associated with
                      25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based
                      on the meta-analysis of observational studies, each
                      1-standard deviation (SD) higher level of 25(OH)D was
                      associated with a $20\%$ lower risk of T2D (relative risk
                      [RR]: 0.80; $95\%$ CI 0.77, 0.84; p < 0.001), but a
                      genetically predicted 1-SD increase in 25(OH)D was not
                      significantly associated with T2D (odds ratio [OR]: 0.96;
                      $95\%$ CI 0.89, 1.03; p = 0.23); this result was consistent
                      across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per
                      1-SD) was associated with a lower risk of T2D (RR: 0.81;
                      $95\%$ CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3
                      (above versus below lower limit of quantification) was
                      positively associated with T2D (RR: 1.12; $95\%$ CI 1.03,
                      1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; $95\%$ CI
                      0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; $95\%$
                      CI 0.93, 1.04; p = 0.53) was causally associated with T2D
                      risk in the MR analysis. Main limitations include the lack
                      of a non-linear MR analysis and of the generalisability of
                      the current findings from European populations to other
                      populations of different ethnicities.Our study found
                      discordant associations of biochemically measured and
                      genetically predicted differences in blood 25(OH)D with T2D
                      risk. The findings based on MR analysis in a large sample of
                      European ancestry do not support a causal association of
                      total 25(OH)D or 25(OH)D metabolites with T2D and argue
                      against the use of vitamin D supplementation for the
                      prevention of T2D.},
      cin          = {C020},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331},
      pnm          = {323 - Metabolic Dysfunction as Risk Factor (POF3-323)},
      pid          = {G:(DE-HGF)POF3-323},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33064751},
      doi          = {10.1371/journal.pmed.1003394},
      url          = {https://inrepo02.dkfz.de/record/164050},
}