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Human Molecular Genetics Advance Access published online on March 15, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn087
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation

Julia H. White1, Mathias Chiano2, Mark Wigglesworth1, Robert Geske1, John Riley2, Nicola White2, Simon Hall3, Guohua Zhu2, Frank Maurio1, Tony Savage1, Wayne Anderson2, Joanna Cordy1, Melissa Ducceschi1, GAIN investigators4, Jorgen Vestbo5 and Sreekumar G Pillai2,*

1 Molecular Discovery Research, GlaxoSmithKline Research and Development,RTP/;NC/; 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 (see the list below) 5 Institute of Preventive Medicine, Kommunehospitalet, Copenhagen, and Department of Respiratory Medicine, Hvidovre University Hospital, Hvidovre, Denmark

* Address for correspondence and reprint requests to Sreekumar G Pillai 5 Moore Drive, laxoSmithKline Research Triangle Park, NC 27709 Sreekumar.g.pillai{at}gsk.com; Phone: (919) 483-1815 FAX: (919) 315-0311

Received November 30, 2007; Revised March 13, 2008; 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, whilst 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.

4Genetics of Asthma International Network Investigators: Kathleen C. Barnesa, Karin Carlsenb, Jorrit Gerritsenc, Warren Lenneyd, Michael Silvermane, Peter Slyf, John Sundyg, John Tsanakash, Andrea von Bergi, Moira Whytej, and Peter J Helms k

aDepartments of Medicine & Epidemiology, Johns Hopkins University, Baltimore, MD, USA (KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program)

bUllevaal University Hospital, Oslo, Norway

cUniversity Medical Center Groningen, University of Groningen, Groningen, Netherlands

dDirectorate of Child Health, Academic Dept of Pediatrics, North Staffordshire Hospital, Stoke on Trent, UK

eUniversity of Leicester, Division of Child Health, Leicester, UK

fCenter for Child Health Research, University of Western Australia, Perth, Australia

gDuke University Medical Center, Durham, NC, USA

hPediatric Respiratory Unit, Hippokration General Hospital, Thessaloniki, Greece

iAbt. Fuer Kinderheilkunde Foschungsinstitut zur Praevention von Allergien und Atemwegserkrankungen im Kindesalter, Wesel, Germany

jAcademic Unit of Respiratory Medicine, University of Sheffield, Sheffield, UK

kDept of Child Health, University of Aberdeen Royal Aberdeen Children's Hospital, Aberdeen, UK


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