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Clinical Trial
. 2009 Jun 15;179(12):1084-90.
doi: 10.1164/rccm.200812-1860OC. Epub 2009 Mar 5.

Assessing the reproducibility of asthma candidate gene associations, using genome-wide data

Angela J Rogers  1 , Benjamin A Raby, Jessica A Lasky-Su, Amy Murphy, Ross Lazarus, Barbara J Klanderman, Jody S Sylvia, John P Ziniti, Christoph Lange, Juan C Celedón, Edwin K Silverman, Scott T Weiss
Affiliations
Clinical Trial

Assessing the reproducibility of asthma candidate gene associations, using genome-wide data

Angela J Rogers et al. Am J Respir Crit Care Med. .

Abstract

Rationale: Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.

Objectives: To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.

Methods: Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.

Measurements and main results: We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin beta(3) [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.

Conclusions: We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true "asthma genes."

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Figures

<b>Figure 1.</b>
Figure 1.
Results for ITGB3. Single-nucleotide polymorphisms (SNPs) in the literature are coded black, SNPs positive in Childhood Asthma Management Program (CAMP) are blue, negative in CAMP are green. (A) The significant association between rs11869835 in CAMP and rs2317676, which is tagged with linkage disequilibrium (LD) of 1.0. (B) Four SNPs that have been previously associated with asthma and were directly tested in CAMP but showed no association. (C) A SNP in the promoter region of ITGB3 that has not been previously evaluated, but was significantly associated in CAMP with a P value of 0.04. LD map is for HapMap (CEU). Negative literature SNPs include only those SNPs reported in studies that published at least one positive association (to ensure adequate power). Image created with the UCSC genome browser (http://genome.ucsc.edu/) and Haploview (http://www.broad.mit.edu/mpg/haploview/).
<b>Figure 2.</b>
Figure 2.
Affymetrix 6.0 versus Illumina 550K coverage of the 160 single-nucleotide polymorphisms (SNPs) previously associated with asthma.
See this image and copyright information in PMC

Comment in

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