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

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.

An Exploration of How Solar Radiation Affects the Seasonal Variation of Human Mortality Rates and the Seasonal Variation in Some Other Common Disorders

“…Since vitamin D is necessary for healthy insulin secretion and reduces abnormal insulin resistance through known mechanisms [123], vitamin D deficiency has long been thought likely to increase type 2 diabetes mellitus (T2DM) risks. That causal effect is supported by MR analyses [124] and by data from the Vitamin D and Type 2 Diabetes Study (D2d), showing up to 70% reductions in T2DM risk after 2.5 years of vitamin D supplementation of those subjects with prediabetes whose serum 25(OH)D values reached ≥100 nmol/l, a level only reached with intakes of 4000 IU/day [125].…”

Effect of obesity on the associations of 25-hydroxyvitamin D with prevalent and incident distal sensorimotor polyneuropathy: population-based KORA F4/FF4 study

“…First, they do not consider recent research indicating the increasing prevalence of DSPN in prediabetes [ 2 , 42 ]. Second, observational studies [ 14 ], Mendelian randomization studies [ 43 ] and several RCTs [ 44 ] suggest a role of low 25(OH)D levels in increasing insulin resistance, decreasing β-cell function and promoting the development of T2D. Thus, even after adjusting for diabetes duration and glycaemic control, it is difficult to know whether the observed associations between low 25(OH)D levels and DSPN are genuine associations or rather an epiphenomenon as previously suggested [ 18 ].…”

Vitamin D, parathyroid hormone, glucose metabolism and incident diabetes in the multiethnic study of atherosclerosis

“…Finally, these results are observational in nature and no conclusions about causation can be made; however, Mendelian randomization studies done in white and Asian populations suggest that the serum-25(OH)D-associated single nucleotide polymorphism (SNP) in the DHCR7-rs12785878 locale is causally associated with risk of diabetes. 44 More research is needed on this and other serum-25(OH)D-associated SNPs.…”