Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations
Authors: John Danesh
Olov Rolandsson
Pilar Amiano
Nasser Laouali
Stephen J Sharp
María-José Sánchez
Domenico Palli
Yvonne T van der Schouw
Isobel D Stewart
Annemieke M W Spijkerman
Rudolf Kaaks
Eleni Sofianopoulou
Maik Pietzner
Elio Riboli
Fulvio Ricceri
Kim Overvad
N Charlotte Onland-Moret
Luca A Lotta
Anja Olsen
Nicholas J Wareham
Anne Tjønneland
Claudia Langenberg
Adam S Butterworth
Eva Ardanaz
Jian&#x27;an Luan
María-Dolores Chirlaque
Thomas E Gundersen
Paul W Franks
Francesca Romana Mancini
Guy Fagherazzi
Núria Sala
Ju-Sheng Zheng
Matthias B Schulze
Peter M Nilsson
Nita G Forouhi
Felix R Day
Eleanor Wheeler
Salvatore Panico
Sabina Sieri
Elisabete Weiderpass
Rosario Tumino
Fumiaki Imamura
Journal: Diabetes Care (2021)
Discipline: CLINICAL MEDICINE
Keywords: Plasma vitamin C; Type 2 diabetes; Mendelian randomization; Genetic variants; Genome-wide association studies
Affiliations: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K., British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K., Vitas Ltd, Oslo, Norway, Ministry of Health of the Basque Government, Public Health Division of Gipuzkoa, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain, Navarra Public Health Institute, Pamplona, Spain, CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain, Digital Epidemiology and e-Health Research Hub, Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg, France, Department of Clinical Sciences, Lund University, Malmö, Sweden, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Center of Epidemiology and Population Health UMR 1018, INSERM, Paris South - Paris Saclay University, Gustave Roussy Institute, Villejuif, France, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Danish Cancer Society Research Center, Copenhagen, Denmark, Department of Public Health, Aarhus University, Aarhus, Denmark, Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy, Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy, Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy, Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, Andalusian School of Public Health, Granada, Spain, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany, 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, Epidemiology and Prevention Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano Via Venezian, Milan, Italy, Cancer Registry and Histopathology Department, Azienda Sanitaria Provinciale (ASP), Ragusa, Italy, International Agency for Research on Cancer, Lyon, France, School of Public Health, Imperial College, London, U.K.

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 &lt; 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. 

Retracted: No

PubPeer comments:
 # **Mendelian randomization study on vitamin C and type 2 diabetes may be misleading** Zheng et al. concluded from their Mendelian randomization study on plasma vitamin C effects on type 2 diabetes risk that u201ca genetically higher level of plasma vitamin C was not significantly associated with type 2 diabetes risk or with glycemic traitsu201d [1, p 103]. In the potential limitations of the study, Zheng wrote that u201cthe low variability of plasma vitamin C explained by these SNPs [single-nucleotide polymorphisms] may limit the statistical power and precision for the MR analysisu201d [1, p 104]. However, Zheng et al. did not consider this issue of power further in their paper. Zheng reported that u201cThe variance of plasma vitamin C explained by the 11 lead SNPs was 1.87% on averageu201d [1, p 102]. From this figure, and the data about the plasma vitamin C means and SD levels available in the Zheng paper, we calculated that their Mendelian randomization study would correspond to the comparison of two population groups of equal size with vitamin C levels of 47.3 vs. 52.7 u03bcM [2]. Such a comparison is not clinically relevant. With low dietary vitamin C intakes, plasma levels can fall below 10u2009u03bcM, whereas with high dietary intakes, plasma levels can increase to over 80u2009u03bcM, see Fig. 1C in [3]. It is important to take into account this eightfold range of plasma vitamin C levels when considering the dose-health relationship in the community, but that was not done by Zheng et al. [1]. Low plasma vitamin C levels are not uncommon. Levels below 11u2009u03bcM were reported, for example, in 25% of men and 16% of women from low-income populations in the UK [4], and in 13% of a US cohort [5]. In many population groups in less developed countries, such low vitamin C levels are even more common [6]. Thus, large segments of the population have vitamin C levels that are less than one fifth of the u201clowu201d plasma vitamin C level corresponding to the Zheng analysis. Based on the large variation in the plasma levels of vitamin C in the population, the most relevant comparison is between low and high plasma levels, e.g., 10u201320u2009u03bcM vs. 60u2013100u2009u03bcM. If a study compares small variations within the high intake range only, the comparison is uninformative about possible effects of vitamin C in the low intake range. Vitamin C may, or may not, influence the risk of type 2 diabetes. However, the study by Zheng et al. is not informative about whether the risk of type 2 diabetes is increased with plasma vitamin C levels in the lower range of 10-20 u03bcM. **References** 1. Zheng JS, Luan J, Sofianopoulou E, Imamura F, Stewart ID, Day FR, Pietzner M, Wheeler E, Lotta LA, Gundersen TE, Amiano P, Ardanaz E, Chirlaque MD, Fagherazzi G, Franks PW, Kaaks R, Laouali N, Mancini FR, Nilsson PM, Onland-Moret NC, Olsen A, Overvad K, Panico S, Palli D, Ricceri F, Rolandsson O, Spijkerman AMW, Su00e1nchez MJ, Schulze MB, Sala N, Sieri S, Tju00f8nneland A, Tumino R, van der Schouw YT, Weiderpass E, Riboli E, Danesh J, Butterworth AS, Sharp SJ, Langenberg C, Forouhi NG, Wareham NJ. Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations. Diabetes Care. 2021;44(1):98-106. https: doi.org 10.2337 dc20-1328 http: www.ncbi.nlm.nih.gov pmc articles pmc7783939 2. Hemilu00e4 H, Chalker E. Assessment of vitamin C effects on pneumonia and COVID-19 using Mendelian randomization: analysis may be misleading. Eur J Clin Nutr. 2022 Feb 14. https: doi.org 10.1038 s41430-022-01091-9 http: www.ncbi.nlm.nih.gov pmc articles pmc8853427 3. Levine M, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. PNAS 1996;93(8):3704-9. https: doi.org 10.1073 pnas.93.8.3704 http: www.ncbi.nlm.nih.gov pmc articles pmc39676 4. Mosdu00f8l A, Erens B, Brunner EJ. Estimated prevalence and predictors of vitamin C deficiency within UK s low-income population. J Public Health (Oxf). 2008;30(4):456-60. https: doi.org 10.1093 pubmed fdn076 5. Schleicher RL, Carroll MD, Ford ES, Lacher DA. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr. 2009;90(5):1252-63. https: doi.org 10.3945 ajcn.2008.27016 6. Rowe S, Carr AC. Global Vitamin C Status and Prevalence of Deficiency: A Cause for Concern? Nutrients. 2020;12(7):2008. https: doi.org 10.3390 nu12072008 http: www.ncbi.nlm.nih.gov pmc articles pmc7400810 ,