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
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Context: Multiple observational studies have reported aninverse relationship between 25-hydroxyvitaminD concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results ofshort- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have beeninconsistent. Objectives and methods: To evaluate the causal role of reduced blood25(OH)D in T2D, here we have performed a bidirectional Mendelian randomizationstudy using 59,890 individuals (5,862 T2D cases and 54,028 controls) fromEuropean and Asian Indian ancestries. We used six known SNPs, including threeT2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluatethe causality and direction of the association between T2D and circulating25(OH)D concentration. Results: Results of the combined meta-analysis of eightparticipating studies showed that a composite score of three T2D SNPs wouldsignificantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10–32; Z score 11.86, which, however, hadno significant association with 25(OH)D status (Beta -0.02nmol/L ± SE0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the geneticallyinstrumented composite score of 25(OH)D lowering alleles significantlydecreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L,p = 7.92 × 10–78; Z score -18.68) but was notassociated 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 anindividual 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 (GCrs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion: Our new data on this bidirectional Mendelianrandomization study suggests that genetically instrumented T2D risk does notcause changes in 25(OH)D levels. However, genetically regulated 25(OH)Ddeficiency due to vitamin D synthesis gene (DHCR7) may influence the risk ofT2D.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 71 |
| Tidsskrift | Nutrition Journal |
| Vol/bind | 20 |
| Udgave nummer | 1 |
| Sider (fra-til) | 1-11 |
| ISSN | 1475-2891 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
PREVEND. PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), The Netherlands organization for health research and development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441), and the Dutch Inter University Cardiology Institute Netherlands (ICIN).
Funding Information:
AIDHS/SDS. This work was supported by NIH grants -R01DK082766, R01DK118427, funded by the National Institute of Health (NIDDK) and NOT-HG-11-009 funded by NHGRI, and a VPR Bridge Grant from University of Oklahoma Health Sciences Center. The authors thank all the participants of AIDHS/SDS and are grateful for their contribution to this study.
Funding Information:
UKHLS. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex. The UK Household Longitudinal Study is funded by the Economic and Social Research Council (ES/H029745/1). The survey was conducted by Nat Cen and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute (WT098051). Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/ .
Funding Information:
1958 BC: This work was supported by the National Health and Medical Research Council, Australia (GNT GNT11123603) and the 25(OH)D measures were funded by the BUPA Foundation. The management of the 1958 Birth Cohort is funded by the Economic and Social Research Council (grant number ES/M001660/1). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). DNA collection was funded by MRC grant G0000934 and cell-line creation by Wellcome Trust grant 068545/Z/02. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of investigators who contributed to generation of the data is available from the Wellcome Trust Case-Control Consortium website. Funding for the project was provided by the Wellcome Trust under the award 076113. This research used resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418.
Funding Information:
IMS. This work was supported by the Wellcome Trust, UK (Grant no. 070797 and Grant no. 083541) which provided funding support for phenotyping and genotyping.
Funding Information:
TWINS UK. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.
Publisher Copyright:
© 2021, The Author(s).
ID: 302552379