Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 1973-1979
DOI: 10.1093/hmg/ddg208
© 2003 Oxford University Press
Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes
1Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 2School of Public Health, University of Sydney, Australia, 3Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 4Hematology Division, Brigham and Women's Hospital, Boston, MA, USA and 5Harvard Partners Center for Genetics and Genomics, Boston, MA, USA
Received April 1, 2003; Revised June 2, 2003; Accepted June 16, 2003
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. Fifty-five nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Non-parametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: (i) percent predicted forced expiratory volume in one second (FEV1); (ii) dose of methacholine resulting in 20% fall in FEV1 from baseline (PC20); (iii) post-bronchodilator percent change in FEV1 (BDPR); (iv) serum eosinophil levels (EOS); and (v) 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.
* To whom correspondence should be addressed at: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. Email: benjamin.raby{at}channing.harvard.edu
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