Asthma and genes encoding components of the vitamin D pathway.
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.


CONCLUSIONS
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.
Bossé
Yohan
Y
Institut universitaire de cardiologie et de pneumologie de Québec, Canada. yohan.bosse@crhl.ulaval.ca
Lemire
Mathieu
M
Poon
Audrey H
AH
Daley
Denise
D
He
Jian-Qing
JQ
Sandford
Andrew
A
White
John H
JH
James
Alan L
AL
Musk
Arthur William
AW
Palmer
Lyle J
LJ
Raby
Benjamin A
BA
Weiss
Scott T
ST
Kozyrskyj
Anita L
AL
Becker
Allan
A
Hudson
Thomas J
TJ
Laprise
Catherine
C
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D001315:Australia; D051940:B7-2 Antigen / Q000235:genetics; D002170:Canada; D002648:Child; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D016753:Interleukin-10 / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics; D014481:United States; D014807:Vitamin D / Q000235:genetics* / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D055815:Young Adult
D051940:B7-2 Antigen; C497964:CD86 protein, human; C508609:IL10 protein, human; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D014807:Vitamin D; D013250:Steroid Hydroxylases; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase