Abstract
BackgroundObservational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations.Methods and findingsData were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%–18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%–23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: −1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data.ConclusionsThe concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.
Highlights
The incidence of type 2 diabetes has increased substantially in both high-income and low- and middle-income countries in recent decades [1]
Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal
The aims of the present study were as follows: (i) to examine the associations of genetic scores for 25(OH)D concentration with the 2 synthesis single nucleotide polymorphism (SNP) (DHCR7-rs12785878 and CYP2R1-rs10741657) versus all available SNPs (2 synthesis SNPs in addition to 1 transport SNP [GC/diastolic blood pressure (DBP)-rs2282679] and 1 catabolism SNP [CYP24A1-rs6013897]) in 82,464 Chinese adults from the China Kadoorie Biobank (CKB) [24]; (ii) to conduct an updated meta-analysis of all genetic studies assessing the effects of genetically instrumented differences in plasma 25 (OH)D concentrations on risk of type 2 diabetes in a primary analysis using the 2 synthesis SNPs and a secondary analysis using all 4 SNPs for 25(OH)D concentration; and (iii) to compare the risks of diabetes associated with equivalent differences in biochemically measured versus genetically instrumented plasma 25(OH)D concentrations
Summary
The incidence of type 2 diabetes has increased substantially in both high-income and low- and middle-income countries in recent decades [1]. Observational studies have reported that higher plasma 25(OH)D concentrations are associated with lower risks of diabetes [5,6,7]. Mendelian randomisation (MR) studies of genetic variants can help to assess the causal relevance of vitamin D status for risk of diabetes. Since genotypes are randomly assigned before birth, associations of genetic variants with risk of diabetes are not constrained by confounding or reverse causality, which limit the interpretation of observational studies [13]. 2 other genetic variants, in the genes GC/DBP (the group-specific component that encodes vitamin D binding protein) and CYP24A1 (which encodes the 24-hydroxylase involved in the clearance of 25[OH]D), have potential pleiotropic effects (S1 Fig) [13]. Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations
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