Abstract
ContextMultiple 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 methodsTo 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.ResultsResults 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.ConclusionOur 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.
Highlights
Type 2 diabetes mellitus (T2D) has become a global health epidemic of twenty-first century
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, hadno significant association with 25(OH)D status (Beta -0.02nmol/L ± SE0.01nmol/L; p = 0.83; Z score -0.21)
The overall distribution of blood 25(OH) D was consistent with previously published reports on these studies, and mean 25(OH)D levels were much lower across South Asian, compared to European cohorts
Summary
Type 2 diabetes mellitus (T2D) has become a global health epidemic of twenty-first century. Vitamin D deficiency increases in conjunction with T2D, Type 1 diabetes mellitus (T1D), obesity, and cardiovascular disease [7]. It may be challenging to rule out the reverse causality accounting for any association. Human genetic information is used by the methodology of Mendelian randomization, which takes account of genetic instruments to provide an unconfounded estimate of the association. The Mendelian randomization strategy is based on the principle that the individual genotypes are randomly assigned and can be used as a genetic instrument with the assumption that their involvement affects the outcome only by modifying the biomarkers (i.e., circulating 25(OH)D) and can be used to test the direction of causation [13, 14]
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