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

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. � 2021, The Author(s).

Keywords

Asian Continental Ancestry Group, Diabetes Mellitus, Type 2, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Vitamin D, Vitamin D Deficiency, 25 hydroxyvitamin D, vitamin D, adult, aged, allele, Article, controlled study, European, female, genetic association, genotype, human, major clinical study, male, Mendelian randomization analysis, non insulin dependent diabetes mellitus, odds ratio, phenotype, quality control, risk assessment, single nucleotide polymorphism, South Asian, statistical analysis, vitamin blood level, Asian continental ancestry group, genetics, meta analysis, vitamin D deficiency