Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations
Zheng, Ju-Sheng; Luan, Jian'an; Sofianopoulou, Eleni; Imamura, Fumiaki; Stewart, Isobel D.; Day, Felix R.; Pietzner, Maik; Wheeler, Eleanor; Lotta, Luca A.; Gundersen, Thomas E.; Amiano, Pilar; Ardanaz, Eva; Chirlaque, Maria-Dolores; Fagherazzi, Guy; Franks, Paul W.; Kaaks, Rudolf; Laouali, Nasser; Mancini, Francesca Romana; Nilsson, Peter M.; Onland-Moret, N. Charlotte; Olsen, Anja; Overvad, Kim; Panico, Salvatore; Palli, Domenico; Ricceri, Fulvio; Rolandsson, Olov; Spijkerman, Annemieke M. W.; Sanchez, Maria-Jose; Schulze, Matthias B.; Sala, Nuria; Sieri, Sabina; Tjonneland, Anne; Tumino, Rosario; van der Schouw, Yvonne T.; Weiderpass, Elisabete; Riboli, Elio; Danesh, John; Butterworth, Adam S.; Sharp, Stephen J.; Langenberg, Claudia; Forouhi, Nita G.; Wareham, Nicholas J.
(2021) Diabetes Care, volume 44, issue 1, pp. 98 - 106
(Article)
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
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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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Keywords: Internal Medicine, Endocrinology, Diabetes and Metabolism, Advanced and Specialised Nursing
ISSN: 0149-5992
Publisher: American Diabetes Association Inc.
Note: Funding Information: Agency for Research on Cancer. The Spanish National cohort is supported by Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, and the Catalan Institute of Oncology – ICO (Spain). Biomarker measurements for vitamin C were funded by the Medical Research Council Cambridge Initiative (RG71466, SJAH/004) and the EPIC-CVD project, which is supported by the European Union Framework 7 (HEALTH-F2-2012-279233), European Research Council (268834), UK Medical Research Council (G0800270 and MR/L003120/1), British Heart Foundation (SP/ 09/002, RG/08/014, and RG13/13/30194) and the UK National Institute for Health Research (Cambridge Biomedical Research Center at the Cambridge University Hospitals National Health Service Foundation Trust). This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. This research has been conducted using the UK Biobank Resource (application number 44448). J.-S.Z. was additionally supported by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Actions grant agreement No 701708, the National Natural Science Foundation of China (81903316), and Zhejiang Ten-thousand Talents Program (2019R52039). Funding Information: Acknowledgments. The authors thank all EPIC participants and staff for their contribution to the study. The authors thank Nicola Kerrison (MRC Epidemiology Unit, Cambridge) for managing the data for the InterAct Project. The authors thank the technical and functional operational teams of the Medical Research Council Epidemiology Unit and laboratory team at VITAS AS, Norway, for the measurements of plasma vitamin C. The authors thank staff from the EPIC-CVD and EPIC-InterAct Coordinating Centers for performing sample preparation and data-handling work, particularly Sarah Spackman (EPIC-CVD Data Manager), and Cambridge Genomic Services for genotyping. Funding. The InterAct project was funded by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following agencies: Medical Research Council Epidemiology Unit MC_UU_ 12015/1 and MC_UU_12015/5 (J.-S.Z., F.I., N.G.F., N.J.W.), and National Institute for Health Research Biomedical Research Center Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014; N.G.F., N.J.W.). The coordina-tionofEPICis financiallysupported bythe European Commission (DG-SANCO) and the International Funding Information: The authors thank all EPIC participants and staff for their contribution to the study. The authors thank Nicola Kerrison (MRC Epidemiology Unit, Cambridge) for managing the data for the InterAct Project. The authors thank the technical and functional operational teams of the Medical Research Council Epidemiology Unit and laboratory team at VITAS AS, Norway, for the measurements of plasma vitamin C. The authors thank staff from the EPIC-CVD and EPIC-InterAct Coordinating Centers for performing sample preparation and data-handling work, particularly Sarah Spackman (EPIC-CVD Data Manager), and Cambridge Genomic Services for genotyping. Funding. The InterAct project was funded by the European Union Sixth Framework Programme (grant number LSHM_CT_2006_037197). In ad-dition, InterAct investigators acknowledge funding from the following agencies: Medical Research Council Epidemiology Unit MC_UU_ 12015/1 and MC_UU_12015/5 (J.-S.Z., F.I., N.G.F., N.J.W.), and National Institute for Health Research Biomedical Research Center Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014; N.G.F., N.J.W.). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The Spanish National cohort is supported by Health Research Fund (FIS)-Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia, and Navarra, and the Catalan Institute of Oncology ? ICO (Spain). Biomarker measurements for vitamin C were funded by the Medical Research Council Cambridge Initiative (RG71466, SJAH/004) and the EPIC-CVD project, which is supported by the European Union Framework 7 (HEALTH-F2-2012-279233), European Research Council (268834), UK Medical Research Council (G0800270 and MR/L003120/1), British Heart Foundation (SP/ 09/002, RG/08/014, and RG13/13/30194) and the UK National Institute for Health Research (Cambridge Biomedical Research Center at the Cambridge University Hospitals National Health Service Foundation Trust). This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. This research has been conducted using the UK Biobank Resource (appli-cation number 44448). J.-S.Z. was additionally supported by the European Union?s Horizon 2020 Research and Innovation Programme under the Marie Sk?odowska-Curie Actions grant agree-ment No 701708, the National Natural Science Foundation of China (81903316), and Zhejiang Ten-thousand Talents Program (2019R52039). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Re-search, or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/ World HealthOrganization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the de-cisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. Publisher Copyright: © 2020 by the American Diabetes Association.
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