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Comprehensive testing of positionally cloned asthma genes in two populations.

Authors: Hersh, CP  Raby, BA  Soto-Quiros, ME  Murphy, AJ  Avila, L  Lasky-Su, J  Sylvia, JS  Klanderman, BJ  Lange, C  Weiss, ST  Celedon, JC 
Citation: Hersh CP, etal., Am J Respir Crit Care Med. 2007 Nov 1;176(9):849-57. Epub 2007 Aug 16.
Pubmed: (View Article at PubMed) PMID:17702965
DOI: Full-text: DOI:10.1164/rccm.200704-592OC

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-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, linkage disequilibrium 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, although 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.

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CRRD Object Information
CRRD ID: 4891923
Created: 2011-01-21
Species: All species
Last Modified: 2011-01-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.