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Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data

¹ Channing Laboratory, Department of Medicine, and ² Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital; ³ Harvard Medical School; ⁴ Harvard School of Public Health; and ⁵ Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Angela J. Rogers, M.D., M.P.H., Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115. E-mail: reajr{at}channing.harvard.edu

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 β₃ [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."

Key Words: asthma • replication • single-nucleotide polymorphism • integrin β₃ • association

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Many genes have been implicated in asthma pathogenesis, yet most prior studies assessed only a few loci within a gene. What This Study Adds to the Field Using genome-wide data in a well-characterized cohort of children with asthma, we performed a comprehensive replication study of 39 candidate genes previously associated with asthma. We found evidence for variant- and gene-level replication for 17 genes, a minority of candidate genes.

 

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				D. L. Nicolae and C. Ober (Too) Great Expectations: The Challenges in Replicating Asthma Disease Genes Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1078 - 1079. [Full Text] [PDF]