Human Molecular Genetics Advance Access published online on July 1, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg208
© 2003 by Oxford University Press
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1 Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, Massachusetts, 02115, U.S.A.
* To whom correspondence should be addressed. E-mail: benjamin.raby{at}channing.harvard.edu.
Chromosome 12q13-24 is among the regions most frequently identified in genome-wide surveys for asthma susceptibility loci, with reports of two distinct clusters of positive linkage signals: one near the interferon gamma locus, the other near the nitric oxide synthase 1 locus. These results suggest that 12q harbors several asthma susceptibility loci. We evaluated this possibility in a subset of families ascertained through the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study. 55 nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Nonparametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: percent predicted forced expiratory volume in one second (FEV1), dose of methacholine resulting in 20% fall in FEV1 from baseline (PC20), post-bronchodilator percent change in FEV1 (BDPR), serum eosinophil levels (EOS), and total serum IgE levels (IgE). Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact p-value = 0.05), airways responsiveness (PC20) at 147 cM (p = 0.01), and indices of pulmonary function (FEV1, BDPR) at 134 cM (p = 0.05 and p < 0.01, respectively). No linkage was observed for the atopy-related phenotypes. We provide further evidence supporting the presence of an asthma-susceptibility locus at the proximal end of chromosome 12q, as well as new evidence for additional loci more distally that account for unique features of the asthma phenotype. Fine-mapping efforts for these loci are warranted.
Article
Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes
2 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
3 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; School of Public Health, University of Sydney, Australia
4 Department of Biostatistics, Harvard School of Public Health, Boston, MA
5 Hematology Division, Brigham and Women's Hospital, Boston, MA
6 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Harvard Partners Center for Genetics and Genomics, Boston, MA
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