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Background 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. Methods 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). Results 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. Conclusion 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.

Tremendous efforts have been invested in research to (1) discover risk factors, biomarkers, and clinical characteristics; (2) understand the pathophysiology and treatment response variability in severe asthma; and (3) design new therapies. However, to combat severe asthma, many questions concerning the pathogenesis of severe asthma, including its natural history, genetic and environmental risk factors, and disease mechanisms, must be answered. In this article we highlight some of the major discoveries concerning the pathogenesis of severe asthma and its therapeutic development. We conclude that discoveries on numerous fronts of severe asthma, from disease heterogeneity, features of airway remodeling, cytokine mediators and signaling pathways underlying disease pathogenesis, disease mechanisms, potential biomarkers, to new therapeutic targets, demonstrate that progress has been made in understanding and developing more effective treatments for this difficult-to-treat disease.

Asthma has generally been defined as a chronic disorder of the lung, with variable airway obstruction, wheeze/cough, and an underlying inflammatory process. However, considerable heterogeneity exists within the population of patients with asthma-like symptoms. Clinically, asthma is being categorized into eosinophilic, neutrophilic, atopic, non-atopic, early onset, and late onset; and aspirin- or exercise-induced in cases with known triggers.

Fibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways. This study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma and severity. Gene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma , severity, and lung function. In refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma , severity, and lung function. Positive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals.

Abstract Genome scans for asthma have identified suggestive or significant linkages on 17 different chromosomes, including chromosome 12, region q13–23, housing the vitamin D receptor (VDR) gene. Through interaction with VDR, 1,25-dihydroxyvitamin D3 mediates numerous biological activities, such as regulation of helper T-cell development and subsequent cytokine secretion profiles. Variants of the VDR have been found to be associated with immune-mediated diseases that are characterized by an imbalance in helper T-cell development, such as Crohn's disease and tuberculosis. The VDR, hence, is a good candidate to be investigated for association with asthma, which is characterized by enhanced helper T-cell type 2 activity. Here, we examined VDR genetic variants in an asthma family-based cohort from Quebec. We report six variants to be strongly associated with asthma and four with atopy (0.0005 ⩽ p ⩽ 0.05). Analysis of the linkage disequilibrium pattern and haplotypes also revealed significant association with both phenotypes (0.0004 ⩽ p ⩽ 0.01). The findings have been replicated by another research team in a second but not in a third cohort. These results identify VDR variants as genetic risk factors for asthma/atopy and implicate a non-human leukocyte antigen immunoregulatory molecule in the pathogenesis of asthma and atopy.

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.