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Respiratory Research

, 10:98

First Online: 24 October 2009Received: 02 June 2009Accepted: 24 October 2009

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.

List of abbreviations usedBHSBusselton Health Study

CAMPChildhood Asthma Management Program

CAPPSCanadian Asthma Primary Prevention Study

CD28CD28 molecule

CD86CD86 molecule

CYP24A1cytochrome P450, family 24, subfamily A, polypeptide 1

CYP27A1cytochrome P450, family 27, subfamily A, polypeptide 1

CYP27B1cytochrome P450, family 27, subfamily B, polypeptide 1

CYP2R1cytochrome P450, family 2, subfamily R, polypeptide 1

FBATfamily based association test

FEV1forced expiratory volume in 1 second

GCvitamin D binding protein

IL10interleukin 10

IL1RL1interleukin 1 receptor-like 1

IL8interleukin 8

LDlinkage disequilibrium

NHSNurses- Health Study

PC20the concentration of methacholine that causes a 20% decline in FEV1

SAGEStudy of Asthma Genes and the Environment

SKIIPSKI interacting protein

SLSJSaguenayLac-Saint-Jean

SNPsingle-nucleotide-polymorphism

VDRvitamin D receptor

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-10-98 contains supplementary material, which is available to authorized users.

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Author: Yohan Bossé - Mathieu Lemire - Audrey H Poon - Denise Daley - Jian-Qing He - Andrew Sandford - John H White - Alan L J

Source: https://link.springer.com/







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