Plasma Vitamin C and type 2 diabetes: Genome-wide association study and mendelian randomization analysis in European populations

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OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 ☓ 10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.


  • Ju Sheng Zheng
  • Jian’An Luan
  • Eleni Sofianopoulou
  • Fumiaki Imamura
  • Isobel D. Stewart
  • Felix R. Day
  • Maik Pietzner
  • Eleanor Wheeler
  • Luca A. Lotta
  • Thomas E. Gundersen
  • Pilar Amiano
  • Eva Ardanaz
  • María Dolores Chirlaque
  • Guy Fagherazzi
  • Rudolf Kaaks
  • Nasser Laouali
  • Francesca Romana Mancini
  • N. Charlotte Onland-Moret
  • Anja Olsen
  • Kim Overvad
  • Salvatore Panico
  • Domenico Palli
  • Fulvio Ricceri
  • Olov Rolandsson
  • Annemieke M.W. Spijkerman
  • María José Sánchez
  • Matthias B. Schulze
  • Núria Sala
  • Sabina Sieri
  • Anne Tjønneland
  • Rosario Tumino
  • Yvonne T. van der Schouw
  • Elisabete Weiderpass
  • Elio Riboli
  • John Danesh
  • Adam S. Butterworth
  • Stephen J. Sharp
  • Claudia Langenberg
  • Nita G. Forouhi
  • Nicholas J. Wareham
External organisations
  • University of Cambridge
  • Westlake University
  • Vitas AS
  • Biodonostia Health Research Institute
  • Health Research Institute of Navarra (IDISNA)
  • CIBER Epidemiology and Public Health (CIBERESP)
  • Navarre Public Health Institute (ISPN)
  • University of Murcia
  • Luxembourg Institute of Health
  • Institut Gustave Roussy
  • German Cancer Research Centre
  • University Medical Center Utrecht
  • Danish Cancer Society Research Center
  • Aarhus University
  • Aalborg University Hospital
  • University of Naples Federico II
  • Institute for Cancer Research, Prevention and Clinical Network (ISPRO)
  • University of Turin
  • Azienda Sanitaria Locale Torino 3
  • Umeå University
  • National Institute for Public Health and the Environment (RIVM)
  • German Institute of Human Nutrition
  • German Center for Diabetes Research
  • University of Potsdam
  • Bellvitge Biomedical Research Institute
  • Istituto Nazionale dei Tumori
  • University of Copenhagen
  • International Agency for Research on Cancer, World Health Organization
  • Imperial College London
  • Wellcome Trust Sanger Institute
  • University of Paris-Saclay
  • Utrecht University
  • Andalusian School Of Public Health (EASP)
  • Catalan Institute of Oncology
  • L'Hospitalet de Llobregat, Barcelona
  • Civic and M.P Arezzo Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Medical Genetics
Original languageEnglish
Pages (from-to)98-106
Number of pages9
JournalDiabetes Care
Issue number1
Publication statusPublished - 2021
Publication categoryResearch