Mendelian randomization analysis demonstrates that low vitamin D is unlikely causative for pediatric asthma

Hysinger, Erik B.; Roizen, Jeffrey D.; Mentch, Frank; Vazquez, Lyam; Connolly, John J.; Bradfield, Jonathan P.; Almoguera, Berta; Sleiman, Patrick; Allen, Julian L.; Levine, Michael A.; Hákonarson, Hákon

doi:10.1016/j.jaci.2016.06.056

Cited by 29 publications

(18 citation statements)

References 10 publications

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“…A large MR study (dealing with >150,000 patients of all ages) showed that serum 25OHD, predicted based on four SNPs, did not influence the risk for (adult or pediatric onset) asthma, atopic dermatitis, or increased serum IgE (78). A similar conclusion was reached in another MR study on the same topic (258), and in another MR study of the GABRIEL asthma database (79). In a small-scale MR analysis of Dutch participants, genetically predicted serum 25OHD was not linked to an inflammation marker, C-reactive protein (80) (Table 2).…”

Section: Immunitysupporting

confidence: 81%

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

et al. 2018

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The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

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Section: Immunitysupporting

confidence: 81%

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

et al. 2018

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“…A recent MR study used a smaller sample of 1,208 cases and 3,877 controls for childhood asthma in individuals of European and non-European ancestry [55] and did not find any evidence for a causal role of vitamin D in asthma. The instruments used in this childhood MR asthma study were only the CYP2R1 and GC SNPs and did not include the SNPs near DHCR7 and CYPR24A1 .…”

Section: Discussionmentioning

confidence: 99%

Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study

et al. 2017

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BackgroundLow 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 findingsWe 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.ConclusionsIn 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.

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“…Finally, the relationship between vitamin D deficiency and childhood and adult asthma is still unclear, with both cross-sectional epidemiological and animal model evidence making this plausible but results from supplementation studies unsupportive (48). MR studies (49,50) have showed no relationship between vitamin D level SNPs and asthma or atopy.…”

Section: Mendelian Randomization Studiesmentioning

confidence: 99%

Genetics and Gene-Environment Interactions in Childhood and Adult Onset Asthma

Morales

Duffy

2019

Front. Pediatr.

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Asthma is a heterogeneous disease that results from the complex interaction between genetic factors and environmental exposures that occur at critical periods throughout life. It seems plausible to regard childhood-onset and adult-onset asthma as different entities, each with a different pathophysiology, trajectory, and outcome. This review provides an overview about the role of genetics and gene-environment interactions in these two conditions. Looking at the genetic overlap between childhood and adult onset disease gives one window into whether there is a correlation, as well as to mechanism. A second window is offered by the genetics of the relationship between each type of asthma and other phenotypes e.g., obesity, chronic obstructive pulmonary disease (COPD), atopy, vitamin D levels, and inflammatory and immune status; and third, the genetic-specific responses to the many environmental exposures that influence risk throughout life, and particularly those that occur during early-life development. These represent a large number of possible combinations of genetic and environmental factors, at least 150 known genetic loci vs. tobacco smoke, outdoor air pollutants, indoor exposures, farming environment, and microbial exposures. Considering time of asthma onset extends the two-dimensional problem of gene-environment interactions to a three-dimensional problem, since identified gene-environment interactions seldom replicate for childhood and adult asthma, which suggests that asthma susceptibility to environmental exposures may biologically differ from early life to adulthood as a result of different pathways and mechanisms of the disease.

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Mendelian randomization analysis demonstrates that low vitamin D is unlikely causative for pediatric asthma

Cited by 29 publications

References 10 publications

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study

Genetics and Gene-Environment Interactions in Childhood and Adult Onset Asthma

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