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Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations

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posted on 17.11.2020, 16:45 by 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, Paul W Franks, Rudolf Kaaks, Nasser Laouali, Francesca Romana Mancini, Peter M Nilsson, N. Charlotte Onland-Moret, Anja Olsen, Kim Overvad, Salvatore Panico, Domenico Palli, Fulvio Ricceri, Olov Rolandsson, Annemieke MW 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
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 difference in plasma vitamin C with type 2 diabetes in up-to 80,983 cases and 842,909 non-cases. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 cases and 11,073 non-cases.

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 standard deviation, 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.

Funding

The InterAct project was funded by the EU FP6 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 [NJW, JZ, FI, NGF], and NIHR Biomedical Research Center Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) [NJW, NGF]. 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 Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain). Biomarker measurements for vitamin C were funded by the MRC 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 and RG/08/014 and RG13/13/30194) and the UK National Institute for Health Research [Cambridge Biomedical Research Center at the Cambridge University Hospitals NHS Foundation Trust]. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. 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

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