. 2021 Jan;44(1):98-106.

doi: 10.2337/dc20-1328. Epub 2020 Nov 17.

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Ju-Sheng Zheng^{1

2}, Jian'an Luan¹, Eleni Sofianopoulou³, Fumiaki Imamura¹, Isobel D Stewart¹, Felix R Day¹, Maik Pietzner¹, Eleanor Wheeler¹, Luca A Lotta¹, Thomas E Gundersen⁴, Pilar Amiano⁵, Eva Ardanaz^{6

7

8}, María-Dolores Chirlaque^{8

9}, Guy Fagherazzi^{10

11}, Paul W Franks¹², Rudolf Kaaks¹³, Nasser Laouali¹¹, Francesca Romana Mancini¹¹, Peter M Nilsson¹², N Charlotte Onland-Moret¹⁴, Anja Olsen^{15

16}, Kim Overvad^{16

17}, Salvatore Panico¹⁸, Domenico Palli¹⁹, Fulvio Ricceri^{20

21}, Olov Rolandsson²², Annemieke M W Spijkerman²³, María-José Sánchez²⁴, Matthias B Schulze^{25

26

27}, Núria Sala²⁸, Sabina Sieri²⁹, Anne Tjønneland^{16

30}, Rosario Tumino³¹, Yvonne T van der Schouw¹⁴, Elisabete Weiderpass³², Elio Riboli³³, John Danesh^{3

34

35

36

37

38}, Adam S Butterworth^{3

34

36

37

38}, Stephen J Sharp¹, Claudia Langenberg¹, Nita G Forouhi³⁹, Nicholas J Wareham³⁹

Affiliations

¹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K.
² Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
³ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
⁴ Vitas Ltd, Oslo, Norway.
⁵ Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain.
⁶ Navarra Public Health Institute, Pamplona, Spain.
⁷ IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
⁸ CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁹ Department of Epidemiology, Regional Health Council, Instituto Murciano de Investigatión Biosanitaria (IMIB)-Arrixaca, Murcia University, Murcia, Spain.
¹⁰ Digital Epidemiology and e-Health Research Hub, Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg, France.
¹¹ Center of Epidemiology and Population Health UMR 1018, INSERM, Paris South - Paris Saclay University, Gustave Roussy Institute, Villejuif, France.
¹² Department of Clinical Sciences, Lund University, Malmö, Sweden.
¹³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁵ Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁶ Department of Public Health, Aarhus University, Aarhus, Denmark.
¹⁷ Department of Cardiology, Aalborg University Hospital, Aarhus, Denmark.
¹⁸ Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
¹⁹ Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
²⁰ Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
²¹ Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Turin, Italy.
²² Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
²³ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
²⁴ Andalusian School of Public Health, Granada, Spain.
²⁵ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
²⁶ German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
²⁷ Institute of Nutrition Science, University of Potsdam, Nuthetal, Germany.
²⁸ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory; Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet of Llobregat, Barcelona, Spain.
²⁹ Epidemiology and Prevention Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano Via Venezian, Milan, Italy.
³⁰ Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.
³¹ Cancer Registry and Histopathology Department, Azienda Sanitaria Provinciale (ASP), Ragusa, Italy.
³² International Agency for Research on Cancer, Lyon, France.
³³ School of Public Health, Imperial College, London, U.K.
³⁴ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, U.K.
³⁵ British Heart Foundation Center of Research Excellence, University of Cambridge, Cambridge, U.K.
³⁶ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, U.K.
³⁷ National Institute for Health Research Cambridge Biomedical Research Center, University of Cambridge and Cambridge University Hospitals, Cambridge, U.K.
³⁸ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, U.K.
³⁹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K. nita.forouhi@mrc-epid.cam.ac.uk nick.wareham@mrc-epid.cam.ac.uk.

PMID: 33203707
PMCID: PMC7783939
DOI: 10.2337/dc20-1328

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Ju-Sheng Zheng et al. Diabetes Care. 2021 Jan.

. 2021 Jan;44(1):98-106.

doi: 10.2337/dc20-1328. Epub 2020 Nov 17.

Authors

Affiliations

¹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K.
² Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
³ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
⁴ Vitas Ltd, Oslo, Norway.
⁵ Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain.
⁶ Navarra Public Health Institute, Pamplona, Spain.
⁷ IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
⁸ CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁹ Department of Epidemiology, Regional Health Council, Instituto Murciano de Investigatión Biosanitaria (IMIB)-Arrixaca, Murcia University, Murcia, Spain.
¹⁰ Digital Epidemiology and e-Health Research Hub, Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg, France.
¹¹ Center of Epidemiology and Population Health UMR 1018, INSERM, Paris South - Paris Saclay University, Gustave Roussy Institute, Villejuif, France.
¹² Department of Clinical Sciences, Lund University, Malmö, Sweden.
¹³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁵ Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁶ Department of Public Health, Aarhus University, Aarhus, Denmark.
¹⁷ Department of Cardiology, Aalborg University Hospital, Aarhus, Denmark.
¹⁸ Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
¹⁹ Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
²⁰ Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
²¹ Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Turin, Italy.
²² Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.
²³ National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
²⁴ Andalusian School of Public Health, Granada, Spain.
²⁵ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
²⁶ German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
²⁷ Institute of Nutrition Science, University of Potsdam, Nuthetal, Germany.
²⁸ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory; Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet of Llobregat, Barcelona, Spain.
²⁹ Epidemiology and Prevention Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano Via Venezian, Milan, Italy.
³⁰ Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.
³¹ Cancer Registry and Histopathology Department, Azienda Sanitaria Provinciale (ASP), Ragusa, Italy.
³² International Agency for Research on Cancer, Lyon, France.
³³ School of Public Health, Imperial College, London, U.K.
³⁴ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, U.K.
³⁵ British Heart Foundation Center of Research Excellence, University of Cambridge, Cambridge, U.K.
³⁶ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, U.K.
³⁷ National Institute for Health Research Cambridge Biomedical Research Center, University of Cambridge and Cambridge University Hospitals, Cambridge, U.K.
³⁸ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, U.K.
³⁹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K. nita.forouhi@mrc-epid.cam.ac.uk nick.wareham@mrc-epid.cam.ac.uk.

PMID: 33203707
PMCID: PMC7783939
DOI: 10.2337/dc20-1328

Abstract

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.

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Figures

**Figure 1**
Design of the study for MR analysis of plasma vitamin C with type 2 diabetes.

**Figure 2**
Volcano plot for the association of the plasma vitamin C genetic score with blood metabolites. Associations of the 11 variant scores and the score excluding the *FADS1* variant were estimated using fixed-effects meta-analyses of individual variant-metabolite associations aligned to the plasma vitamin C-raising alleles. The horizontal dashed line indicates a Bonferroni-corrected significance threshold (corrected for 175 tests), and diameters of points are proportional to abs(effect size)*50, where “abs” is the function to calculate the absolute value of the effect size.

**Figure 3**
Genetically predicted and observational associations of plasma vitamin C with type 2 diabetes. A: MR and observational estimate of plasma vitamin C with type 2 diabetes. MR estimate of the association between a genetically predicted difference of 1 SD in plasma vitamin C and type 2 diabetes (odds ratio [OR]) was determined using different methods: inverse-variance weighted, MR Egger, and weighted median. Ten lead genetic variants (excluding *FADS1* variant due to pleiotropic effects) identified in the present genome-wide meta-analysis were used for the MR analysis. Observational estimate of the association of plasma vitamin C with type 2 diabetes (hazard ratio [HR]) was estimated in EPIC-InterAct using Prentice-weighted Cox regression, adjusting for potential confounders. B: Scatter plot of genetic association with type 2 diabetes and genetic association with the plasma vitamin C levels.

See this image and copyright information in PMC

References

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Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Affiliations

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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