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A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

Bejar, Cynthia A and Goyal, Shiwali and Afzal, Shoaib and Mangino, Massimo and Zhou, Ang and van der Most, Peter J and Bao, Yanchun and Gupta, Vipin and Smart, Melissa C and Walia, Gagandeep K and Verweij, Niek and Power, Christine and Prabhakaran, Dorairaj and Singh, Jai Rup and Mehra, Narinder K and Wander, Gurpreet S and Ralhan, Sarju and Kinra, Sanjay and Kumari, Meena and de Borst, Martin H and Hyppönen, Elina and Spector, Tim D and Nordestgaard, Børge G and Blackett, Piers R and Sanghera, Dharambir K (2021) 'A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.' Nutrition Journal, 20 (1). 71-. ISSN 1475-2891

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Context Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. Objectives and methods To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. Results Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10–32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10–78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

Item Type: Article
Uncontrolled Keywords: Humans; Diabetes Mellitus, Type 2; Vitamin D Deficiency; Vitamin D; Polymorphism, Single Nucleotide; Mendelian Randomization Analysis; Asians
Divisions: Faculty of Science and Health
Faculty of Social Sciences
Faculty of Science and Health > Mathematical Sciences, Department of
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 01 Sep 2021 15:14
Last Modified: 23 Sep 2022 19:46

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