medwireNews: Genetic analyses indicate that there is no causal association between vitamin D levels and type 2 diabetes, even though the association appears to be strong in observational data.
The results of the Mendelian randomization (MR) analysis are in line with those of the randomized D2d trial, previously reported by medwireNews, which found no effect of vitamin D supplementation on type 2 diabetes risk.
Indeed, Ju-Sheng Zheng (University of Cambridge, UK) and co-investigators say: “The current findings together with other evidence from randomised controlled trials do not support the use of vitamin D supplementation for the prevention of type 2 diabetes.”
In the first part of their study, Zheng and team conducted a meta-analysis of nine genome-wide association studies in participants of European decent and identified 10 genetic loci associated with total 25-hydroxyvitamin D (25[OH]D), seven loci associated with the 25(OH)D metabolite 25(OH)D3, and three loci associated with the empiric form of the molecule, C3-epi-25(OH)D3.
Of these, six were previously known (in GC, CYP2R1, NADSYN1/DHCR7, AMDHD1, SEC23A, and CYP24A1) and four were newly discovered (in PADI1, CRCT1, UGT1A5, and SULT2A1).
The researchers then used MR analysis to investigate the causal association of the 25(OH)D metabolites with type 2 diabetes among 80,983 individuals with type 2 diabetes and 842,909 controls.
They found that total 25(OH)D, 25(OH)D3, and C3-epi-25(OH)D3 were not genetically correlated with type 2 diabetes nor with glycated hemoglobin, insulin resistance, beta cell function, fasting insulin, fasting glucose, and 2-hour glucose.
Furthermore, the 10 SNPs identified only explained around 3–4% of the variance in type 2 diabetes risk.
Zheng et al also conducted a meta-analysis of observational study data, which suggested that each standard deviation (SD) increase in 25(OH)D level was associated with a significant 20% reduction in the risk for type 2 diabetes. For the individual metabolites, each SD increase in 25(OH)D3 level was associated with a significant 19% decrease in type 2 diabetes risk, whereas a C3-epi-25(OH)D3 level above versus below the lower limit of quantification was associated with a significant 12% increased risk.
Writing in PLOS Medicine, the authors say that the “reasons for the difference between the observational and MR findings remain unclear, but it may be that adjustment for adiposity, diet, and physical activity using a single imprecise measure of these variables at baseline only partially reduced the confounding effects of these variables.”
The add that “including populations from different ethnic groups with varying distributions of 25(OH)D levels; and further increasing sample size and hence statistical power for conducting MR analysis of non-linear associations” are among the next steps needed to address “unresolved issues.”
Nonetheless, Zheng and team conclude that “focusing on population-wide supplementation to raise blood vitamin D levels is not likely to be an effective strategy for the prevention of [type 2 diabetes] in European populations.”
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