نبذة مختصرة : Background Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. Methods and findings We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90–1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69–1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92–1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was −0.40 (95% CI −1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. Conclusions In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.
In a Mendelian randomization analysis, J. Brent Richards and colleagues investigate possible relations between genetic elements associated with vitamin D levels and atopic susceptibility.
Author summary Why was this study done? Observational epidemiological studies have reported associations of low vitamin D levels with risk of asthma, atopic dermatitis, and elevated immunoglobulin E (IgE) levels. However, these studies are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are genuine. The randomized controlled trials published to date on this topic have been inconclusive. If vitamin D insufficiency did cause atopic diseases, this would be of clinical relevance, since vitamin D insufficiency is common and safely correctable. What did the researchers do and find? We applied a Mendelian randomization study design, which greatly limits bias due to confounding and prevents bias due to reverse causation, to understand if vitamin D levels are associated with a higher risk of adult and pediatric asthma, atopic dermatitis, or elevated IgE levels. Despite high statistical power, our study showed no evidence of an unconfounded association between vitamin D and the studied outcomes. What do these findings mean? Our findings suggest that the previous epidemiological associations between vitamin D and atopic diseases could be due to confounding. Efforts to increase vitamin D levels will probably not result in decreased risk of adult and pediatric asthma, atopic dermatitis, or elevated IgE levels.
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