title: Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation.
abstract: 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.
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline Research and Development, RTP, NC, USA/Stevenage, UK.
authors.forename: Julia H
authors.initials: JH
authors.lastname: White
authors.forename: Mathias
authors.initials: M
authors.lastname: Chiano
authors.forename: Mark
authors.initials: M
authors.lastname: Wigglesworth
authors.forename: Robert
authors.initials: R
authors.lastname: Geske
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Nicola
authors.initials: N
authors.lastname: White
authors.forename: Simon
authors.initials: S
authors.lastname: Hall
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhu
authors.forename: Frank
authors.initials: F
authors.lastname: Maurio
authors.forename: Tony
authors.initials: T
authors.lastname: Savage
authors.forename: Wayne
authors.initials: W
authors.lastname: Anderson
authors.forename: Joanna
authors.initials: J
authors.lastname: Cordy
authors.forename: Melissa
authors.initials: M
authors.lastname: Ducceschi
authors.forename: Jorgen
authors.initials: J
authors.lastname: Vestbo
authors.forename: Sreekumar G
authors.initials: SG
authors.lastname: Pillai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D002460:Cell Line; D002648:Child; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D017299:Rod Opsins / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C085460:CHML protein, human; C430099:OPN3 protein, human; D034741:RNA, Small Interfering; D017299:Rod Opsins