Asthma and genes encoding components of the vitamin D pathway
1 Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
2 Laval University Hospital Research Center (CRCHUL), Québec, Canada
3 Ontario Institute for Cancer Research, Toronto, Canada
4 The Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
5 Harvard Medical School, Boston, MA, USA
6 James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St Paul's Hospital, University of British Columbia, Vancouver, Canada
7 Departments of Physiology and Medicine, McGill University, Montreal, Canada
8 West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Western Australia
9 Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Western Australia
10 UWA Centre for Genetic Epidemiology and Biostatistics, The University of Western Australia, Western Australia
11 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
12 The Center for Genomics Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
13 Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Canada
14 Université du Québec à Chicoutimi, Chicoutimi, Canada
15 Community Genomic Medicine Centre, University of Montreal, Chicoutimi University Hospital, Chicoutimi, Canada
Respiratory Research 2009, 10:98 doi:10.1186/1465-9921-10-98Published: 24 October 2009
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.