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Characterization of a Common Susceptibility Locus for Asthma-Related Traits
Tarja Laitinen,1,2 Anne Polvi,2 Pia Rydman,1 Johanna Vendelin,1,2 Ville Pulkkinen,1 Paula Salmikangas,1 Siru Mäkelä,2 Marko Rehn,1 Asta Pirskanen,1 Anna Rautanen,4 Marco Zucchelli,5 Harriet Gullstén,2,5 Marina Leino,6 Harri Alenius,6 Tuula Petäys,7 Tari Haahtela,7 Annika Laitinen,3 Catherine Laprise,9 Thomas J. Hudson,10 Lauri A. Laitinen,8 Juha Kere*2,5
Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein–coupled receptor named GPRA (G protein–coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism–tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of 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@biosci.ki.se
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on of a Common Susceptibility Locus for Asthma.doc (195.5k) 两外两篇相关文献：
１．Asthma is an increasingly prevalent condition with both environmental and genetic influences. Only a handful of candidate genes showing direct association have been identified, and even fewer have provided any clear insight into the pathophysiology. In a study of three independent patient cohorts presenting with asthma or allergy from Finland and Canada, Laitinen et al. (p. 300; see the news story by Couzin) identified inherited single nucleotide polymorphism (SNP) haplotypes in a region of chromosome 7p. Genotyping of these risk-associating haplotypes helped guide identification of a candidate gene encoding a G protein-coupled receptor, designated GPRA. This gene has coding SNPs that associate strongly with both asthma and the allergic phenotype, and apparently also cause alterations in expression, and possibly function, of the protein.
２．Two New Asthma Genes Uncovered
Jennifer Couzin
A painstaking, decade-long hunt spanning two continents has led a team of Finnish scientists to two new asthma genes, described on page 300.
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167_185.zip (255.44k) [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-05-30 19:27
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