Project description:Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy.Eleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway (CYP27A1, CYP27B1, CYP2R1, CYP24A1, GC) and six that are known to be transcriptionally regulated by vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP).A number of SNPs in the IL10, CYP24A1, CYP2R1, IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations.A number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.
Project description:Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH)2D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH)2D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.
Project description:BackgroundEpidemic thunderstorm asthma (ETSA) severely affected Melbourne, Australia in November 2016. There is scant literature on the natural history of individuals affected by ETSA.ObjectiveA multicentre 12-month prospective observational study was conducted assessing symptomatology and behaviors of ETSA-affected individuals.MethodsWe used a structured phone questionnaire to assess asthma symptom frequency, inhaled preventer use, asthma action plan ownership and healthcare utilization over 12 months since the ETSA. Analysis of results included subgroup analyses of the "current," "past," "probable," and "no asthma" subgroups defined according to their original 2016 survey responses.ResultsFour hundred forty-two questionnaires were analyzed. Eighty percent of individuals reported ongoing asthma symptoms at follow-up, of which 28% were affected by asthma symptoms at least once a week. Risk of persistent asthma symptoms was significantly higher in those with prior asthma diagnosis, current asthma, and probable undiagnosed asthma (all p < 0.01). Of 442 respondents, 53% were prescribed inhaled preventers, of which 51% were adherent at least 5 days a week. Forty-two percent had a written asthma action plan and 16% had sought urgent medical attention for asthma in the preceding year.ConclusionsFollowing an episode of ETSA, patients experience a pivotal change in asthma trajectory with both loss of asthma control and persistence of de novo asthma. Suboptimal rates of inhaled preventer adherence and asthma action plan ownership may contribute to asthma exacerbation risk and susceptibility to future ETSA episodes. Longer-term follow-up is needed to determine the extent and severity of this apparent change.
Project description:Purpose of reviewTo review the literature of the past 18 months (April 2017 through September, 2018) relating to vitamin D and childhood asthma.Recent findingsA combined analysis of two clinical trials of maternal vitamin D supplementation trials showed a significant protective effect of vitamin D supplementation trials in the primary prevention of asthma and recurrent wheeze up to age 3 years. Secondary analyses from these trials have also suggested that initial maternal vitamin D status could affect the response to supplementation during pregnancy, with the biggest protective effect in children born to mothers with initial 25hydroxyvitamin D (25OHD) levels of at least 30 ng/ml. A postnatal, 6-month vitamin D supplementation trial in black, premature babies showed a 34% decreased risk of recurrent wheezing at 1 year among the infants who received supplementation. An individual patient data meta-analysis of published clinical trials concluded that vitamin D supplementation decreased the risk of asthma exacerbations in those with 25OHD levels less than 10 ng/ml. Results of observational analyses on primary prevention of asthma and in prevention of exacerbations remain mixed, with the bulk of the evidence suggesting that there is a protective effect of higher vitamin D levels.SummaryEvidence continues to accumulate that vitamin D supplementation helps to prevent the development of asthma and recurrent wheeze in early life, and may also help in the management of asthma. The level(s) of circulating vitamin D that maximizes these effects remains to be identified.
Project description:Vitamin D is a steroid hormone traditionally connected to phosphocalcium metabolism. The discovery of pleiotropic expression of its receptor and of the enzymes involved in its metabolism has led to the exploration of the other roles of this vitamin. The influence of vitamin D on autoimmune disease-namely, on autoimmune thyroid disease-has been widely studied. Most of the existing data support a relationship between vitamin D deficiency and a greater tendency for development and/or higher titers of antibodies linked to Hashimoto's thyroiditis, Graves' disease, and/or postpartum thyroiditis. However, there have also been some reports contradicting such relationships, thus making it difficult to establish a unanimous conclusion. Even if the existence of an association between vitamin D and autoimmune thyroid disease is assumed, it is still unclear whether it reflects a pathological mechanism, a causal relationship, or a consequence of the autoimmune process. The relationship between vitamin D's polymorphisms and this group of diseases has also been the subject of study, often with divergent results. This text presents a review of the recent literature on the relationship between vitamin D and autoimmune thyroid disease, providing an analysis of the likely involved mechanisms. Our thesis is that, due to its immunoregulatory role, vitamin D plays a minor role in conjunction with myriad other factors. In some cases, a vicious cycle is generated, thus contributing to the deficiency and aggravating the autoimmune process.
Project description:Vitamin D deficiency and asthma are common conditions that share risk factors such as African American ethnicity, inner-city residence, and obesity. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between vitamin D status and asthma or asthma morbidity, including potential protective mechanisms such as antiviral effects and enhanced steroid responsiveness. Because most published epidemiologic studies of vitamin D and asthma or asthma morbidity are observational, a recommendation for or against vitamin D supplementation as preventive or secondary treatment for asthma is not advisable and must await results of ongoing clinical trials. Should these trials confirm a beneficial effect of vitamin D, others will be needed to assess the role of vitamin D supplementation to prevent or treat asthma in different groups such as infants, children of school age, and ethnic minorities.
Project description:Rationale: Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions.Objectives: To determine whether vitamin D metabolism is altered in asthma or COPD.Methods: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D3, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.Measurements and Main Results: The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L; P = 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both presupplementation and postsupplementation (P ≤ 0.005). Intergroup differences in 1α,25(OH)2D3-inducible gene expression signatures were modest and variable if statistically significant.Conclusions: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.