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Characterization of a Common Susceptibility Locus for Asthma-Related Traits
Tarja Laitinen,1,2Anne Polvi,2Pia Rydman,1Johanna Vendelin,1,2Ville Pulkkinen,1Paula Salmikangas,1Siru Mäkelä,2Marko Rehn,1Asta Pirskanen,1Anna Rautanen,4Marco Zucchelli,5Harriet Gullstén,2,5Marina Leino,6Harri Alenius,6Tuula Petäys,7Tari Haahtela,7Annika Laitinen,3Catherine Laprise,9Thomas J. Hudson,10Lauri A. Laitinen,8Juha Kere*2,5
Susceptibility to asthma depends on variation at an unknownnumber of genetic loci. To identify susceptibility genes onchromosome 7p, we adopted a hierarchical genotyping design,leading to the identification of a 133-kilobase risk-conferringsegment containing two genes. One of these coded for an orphanG protein–coupled receptor named GPRA (G protein–coupledreceptor for asthma susceptibility), which showed distinct distributionof protein isoforms between bronchial biopsies from healthyand asthmatic individuals. In three cohorts from Finland andCanada, single nucleotide polymorphism–tagged haplotypesassociated with high serum immunoglobulin E or asthma. The murineortholog of GPRA was up-regulated in a mouse model of ovalbumin-inducedinflammation. Together, these data implicate GPRA in the pathogenesisof atopy and asthma.
1 GeneOS Limited, 00251 Helsinki, Finland. 2 Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland. 3 Department of Anatomy, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland. 4 Finnish Genome Center, University of Helsinki, 00014 Helsinki, Finland. 5 Department of Biosciences at Novum and Clinical Research Centre, Karolinska Institutet, 14157 Huddinge, Sweden. 6 Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, 00251 Helsinki, Finland. 7 Department of Allergological Diseases, Helsinki University Central Hospital, 00029 Helsinki, Finland. 8 Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland. 9 Community Genomic Medicine Centre, Université du Québec à Chicoutimi, Saguenay, Quebec G7H 2B1 Canada. 10 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4 Canada.
* To whom correspondence should be addressed. E-mail: juha.kere{at}biosci.ki.se
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Physiol Genomics
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Human chromosome 7 circa 2004: a model for structural and functional studies of the human genome.
