Asthma and genes encoding components of the vitamin D pathway

Yohan Bossé,Mathieu Lemire,Thomas J Hudson,John H White,Allan Becker,William Arthur Musk,Andrew Sandford,Denise Daley,Benjamin A Raby,Catherine Laprise,Alan L James,Scott T Weiss,Jian-Qing He,Lyle J Palmer,Audrey H Poon,Anita L Kozyrskyj

doi:10.1186/1465-9921-10-98

Abstract

BackgroundGenetic 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.MethodsEleven 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).ResultsA 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.ConclusionA 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.

Highlights

Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy
A number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy
The minor allele frequencies were very similar between the two populations with a mean difference of 2% and the largest difference was 16% for SNP rs4308217 located in the CD86 gene

Summary

Introduction

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. Major efforts are currently underway to validate these genes in larger populations as well as to identify novel genes using new technology-driven approaches such as genome-wide single-nucleotide-polymorphism (SNP) association studies [6,7,8]. Many genes involved in inflammation and immunoregulation pathways have been associated with asthma [3]. The vitamin D pathway has emerged as a new pathway contributing to the outcome of immune responses [9,10,11,12]. The VDR ligand/receptor complex alters the transcription rate of many genes involved in a wide spectrum of biological responses [14]

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Discussion

Conclusion