Human Molecular Genetics Advance Access originally published online on March 15, 2008
Human Molecular Genetics 2008 17(13):1890-1903; doi:10.1093/hmg/ddn087
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Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation
1 Molecular Discovery Research, GlaxoSmithKline Research and Development, RTP, NC, USA/Stevenage, UK 2 Genetics, GlaxoSmithKline, Research Triangle Park, NC, USA/Stevenage, UK 3 Respiratory Center for Excellence in Drug Discovery, GlaxoSmithKline, Stevenage, UK 4 Genetics of Asthma International Network Investigators 5 Institute of Preventive Medicine, Kommunehospitalet, Copenhagen, and Department of Respiratory Medicine, Hvidovre University Hospital, Hvidovre, Denmark
* To whom correspondence should be addressed at: 5 Moore Drive, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. Tel: +1 9194831815; Fax: +1 9193150311; Email: sreekumar.g.pillai{at}gsk.com
Received November 30, 2007; Accepted March 13, 2008
Asthma is a multifactorial disease, in which the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Using a genome-wide scan for linkage in a population comprising of Danish families, we identified a novel linked locus on chromosome 1qter (LOD 3.6, asthma) and supporting evidence for this locus was identified for both asthma and atopic-asthma phenotypes in the GAIN (Genetics of Asthma International Network) families. The putative susceptibility gene was progressively localized to a 4.5 Mb region on chromosome 1q adjacent to the telomere, through a series of genotyping screens. Further screening using the pedigree-based association test (PBAT) identified polymorphisms in the OPN3 and CHML genes as being associated with asthma and atopic asthma after correcting for multiple comparisons. We observed that polymorphisms flanking the OPN3 and CHML genes wholly accounted for the original linkage in the Danish population and the genetic association was also confirmed in two separate studies involving the GAIN families. OPN3 and CHML are unique genes with no known function that are related to the pathophysiology of asthma. Significantly, analysis of gene expression at both RNA and protein levels, clearly demonstrated OPN3 expression in lung bronchial epithelia as well as immune cells, while CHML expression appeared minimal. Moreover, OPN3 down-regulation by siRNA knock-down in Jurkat cells suggested a possible role for OPN3 in modulation of T-cell responses. Collectively, these data suggest that OPN3 is an asthma susceptibility gene on 1qter, which unexpectedly may play a role in immune modulation.
Genetics of Asthma International Network Investigators: Kathleen C. Barnes—Departments of Medicine & Epidemiology, Johns Hopkins University, Baltimore, MD, USA; Karin Carlsen—Ullevaal University Hospital, Oslo, Norway; Jorrit Gerritsen—University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Warren Lenney—Directorate of Child Health, Academic Department of Pediatrics, North Staffordshire Hospital, Stoke-on-Trent, UK; Michael Silverman—University of Leicester, Division of Child Health, Leicester, UK; Peter Sly—Center for Child Health Research, University of Western Australia, Perth, Australia; John Sundy—Duke University Medical Center, Durham, NC, USA; John Tsanakas—Pediatric Respiratory Unit, Hippokration General Hospital, Thessaloniki, Greece; Andrea von Berg—Abt. Fuer Kinderheilkunde Foschungsinstitut zur Praevention von Allergien und Atemwegserkrankungen im Kindesalter, Wesel, Germany; Moira Whyte—Academic Unit of Respiratory Medicine, University of Sheffield, Sheffield, UK; Peter J. Helms—Department of Child Health, University of Aberdeen Royal Aberdeen Children's Hospital, Aberdeen, UK.