Mendelian Randomization Study Shows Vitamin D Deficiency Not Associated With T1D

Genetically decreased vitamin D levels are unlikely to have a large effect on risk of type 1 diabetes (T1D) among European populations, according to results of a Mendelian randomization (MR) study published in PLOS Medicine.

Although several observational studies have suggested an association between T1D and serum 25 hydroxyvitamin D (25OHD) deficiency, evidence from large randomized controlled trials (RCTs) is lacking. In addition, observational studies “are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are accurate,” the authors wrote.

Currently, there are no known therapies that can be used to prevent T1D, while prevalence under the age of 14 years old is expected to rise by 3% annually worldwide. Furthermore, “the prevalence of vitamin D insufficiency is estimated to be 43% in the general population and is also increasing,” researchers noted.

To better understand the causal relationship between vitamin D and T1D, investigators performed a 2-sample MR study using single nucleotide polymorphisms (SNPs) from the largest genome-wide association study (GWAS) on vitamin D to date (n= 443,734).

“To satisfy the first MR assumption, which requires that the instrument (SNP) robustly associates with the exposure (25OHD level), we chose as instruments SNPs which were associated with 25OHD levels at a level of genome-wide significance (P < 6.6 × 10−9),” authors said.

Researchers then extracted estimates of the effects of the 23OHD-associated variants on T1D from a GWAS meta-analysis of 12 European studies, which included 9358 cases and 15,705 controls.

A total of 69 lead common independent SNPs, which account for 3.1% of the variance in vitamin D levels, were used as instruments in the studies. However, 8 were absent in the T1D GWAS and were thus replaced by proxies in high linkage disequilibrium (LD) (r2 > 0.7). Specifically, the study of 25,063 individuals “had a power of 80% power to exclude effects on T1D as small as an OR of 1.23 per 1 SD change in 25OHD on the log scale and a power of 100% to exclude effects as small as an OR of 1.4).”

Analyses revealed:

• No evidence supporting a causal association between 25OHD levels and risk of T1D (inverse-variance weighted [IVW] MR OR, 1.09; 95% CI, 0.86-1.40; P = 0.48 per 1 SD decrease in standardized log-trans- formed 25OHD)
• 1 SD change in standardized natural-log transformed 25OHD levels was estimated to correspond to a change in 25OHD levels of 40.9 nmol/l in vitamin D-sufficient individuals (defined as having 25OHD levels of 70 nmol/l), of 29.2 nmol/l in vitamin D-insufficient individuals (25OHD levels of 50 nmol/l), and of 14.6 nmol/l in vitamin D-deficient individuals (25OHD levels of 25 nmol/l)
• An enrichment in SNPs associated with certain trait categories (among 1641 SNP-trait associations with 494 individual traits found, 246 associations with blood cell counts were observed, 250 associations with body composition traits, and 213 associations with serum lipids)

Similar results were found when researchers used 3 pleiotropy robust MR methods (MR-Egger, weighted median, and mode-based estimate) and conducted sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes.

Levels of vitamin D measures were comparable to the effect of a conventional dose of vitamin D supplementation in deficient individuals.

“Our findings confidently exclude large effects (OR >1.40), given the sufficient statistical power and the consistency of the estimates using different MR methods and in the sensitivity analyses,” authors wrote. “However, the relatively large confidence intervals of our MR result suggests that small effects cannot be excluded, and further evidence is needed to investigate such effects.”

Researchers hypothesize previous associations may have been due to confounding factors including latitude and exposure to sunlight. As the exact function of most of the SNPs included in the study is unknown, residual bias is possible, marking a limitation. Results may also not be generalizable to populations residing outside of the European continent.

“Until further evidence from large RCTs, we cannot suggest the use of vitamin D supplements as a strategy to prevent T1D in individuals at risk, for instance siblings or offspring of people with T1D,” said lead study author Despoina Manousaki, MD.

Reference

Manousaki D, Harroud A, Mitchell RE, et al. Vitamin D levels and risk of type 1 diabetes: a Mendelian randomization study. PloS Med. Published online February 25, 2021. doi:10.1371/journal. pmed.1003536