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

Cynthia A Bejar; Shiwali Goyal; Shoaib Afzal; Massimo Mangino; Ang Zhou; Peter J van der Most; Yanchun Bao; Vipin Gupta; Melissa C Smart; Gagandeep K Walia; Niek Verweij; Christine Power; Dorairaj Prabhakaran; Jai Rup Singh; Narinder K Mehra; Gurpreet S Wander; Sarju Ralhan; Sanjay Kinra; Meena Kumari; Martin H de Borst; Elina Hyppönen; Tim D Spector; Børge G Nordestgaard; Piers R Blackett; Dharambir K Sanghera

doi:10.1186/s12937-021-00725-1

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

Nutr J. 2021 Jul 27;20(1):71. doi: 10.1186/s12937-021-00725-1.

Authors

Cynthia A Bejar¹, Shiwali Goyal¹, Shoaib Afzal^{2

3

4}, Massimo Mangino^{5

6}, Ang Zhou⁷, Peter J van der Most⁸, Yanchun Bao⁹, Vipin Gupta¹⁰, Melissa C Smart⁹, Gagandeep K Walia¹¹, Niek Verweij¹², Christine Power¹³, Dorairaj Prabhakaran¹¹, Jai Rup Singh¹⁴, Narinder K Mehra¹⁵, Gurpreet S Wander¹⁶, Sarju Ralhan¹⁶, Sanjay Kinra¹⁷, Meena Kumari⁹, Martin H de Borst¹², Elina Hyppönen^{7

13

18}, Tim D Spector⁵, Børge G Nordestgaard^{2

3

4}, Piers R Blackett^{19

20}, Dharambir K Sanghera^{21

22

23

24

25}

Affiliations

¹ Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, OK, 73104, OK City, USA.
² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³ The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
⁶ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, SE1 9RT, London, UK.
⁷ Australian Center for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.
⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, NL, The Netherlands.
⁹ Department of Mathematical Sciences, University of Essex, Colchester, UK.
¹⁰ Department of Anthropology, University of Delhi, New Delhi, India.
¹¹ Public Health Foundation of India, Gurgaon, India.
¹² Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹³ Population, Policy and Practice, Institute of Child Health, University College London, London, WC1N 1EH, UK.
¹⁴ Department of Human Genetics, Central University of Punjab, Bathinda, Punjab, India.
¹⁵ Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences and Research, New Delhi, India.
¹⁶ Department of Cardiology, Hero DMC Heart Institute, Ludhiana, India.
¹⁷ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁸ Australian Centre for Precision Health, South Australian Health and Medical Research Institute, Adelaide, Australia.
¹⁹ Department of Pediatrics, Section of Pediatric Endocrinology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
²⁰ Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
²¹ Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, OK, 73104, OK City, USA. Dharambir-sanghera@ouhsc.edu.
²² Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Dharambir-sanghera@ouhsc.edu.
²³ Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Dharambir-sanghera@ouhsc.edu.
²⁴ Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Dharambir-sanghera@ouhsc.edu.
²⁵ Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Dharambir-sanghera@ouhsc.edu.

Abstract

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Asian People / genetics
Diabetes Mellitus, Type 2* / genetics
Humans
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Vitamin D
Vitamin D Deficiency* / genetics

Substances

Vitamin D

Abstract

Publication types

MeSH terms

Substances

Grants and funding