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Published ahead of print on August 16, 2007, doi:10.1164/rccm.200704-592OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 9, November 2007, 849-857

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Submitted on April 17, 2007
Accepted on August 16, 2007

Comprehensive Testing of Positionally Cloned Asthma Genes in Two Populations

Craig P Hersh1*, Benjamin A Raby1, Manuel E Soto-Quiros2, Amy J Murphy3, Lydiana Avila2, Jessica Lasky-Su3, Jody S Sylvia4, Barbara J Klanderman3, Christoph Lange5, Scott T Weiss3, and Juan C Celedon1

1 Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 2 Division of Pediatric Pulmonology, Hospital Nacional de Ninos, San Jose, Costa Rica, 3 Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 4 Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA, 5 Channing Laboratory and Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: craig.hersh{at}channing.harvard.edu.

Rationale: Replication of gene-disease associations has become a requirement in complex trait genetics. Objectives: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning. Methods: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels. Measurements and Main Results: Despite differing ancestries, LD patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, though the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes. Conclusions: These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.
Key words: Bronchial Hyperreactivity, Immunoglobulin E, Linkage Disequilibrium, NPSR1, Single Nucleotide Polymorphism




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