Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 304 (5668): 300-304

Copyright © 2004 by the American Association for the Advancement of Science

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

Abstract: 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{at}

Variants of Asthma and Chronic Obstructive Pulmonary Disease Genes and Lung Function Decline in Aging.
A. H. Poon, E. A. Houseman, L. Ryan, D. Sparrow, P. S. Vokonas, and A. A. Litonjua (2013)
J Gerontol A Biol Sci Med Sci
   Abstract »    Full Text »    PDF »
Truncation of MIMT1 Gene in the PEG3 Domain Leads to Major Changes in Placental Gene Expression and Stillbirth in Cattle.
K. Flisikowski, H. Venhoranta, S. Bauersachs, R. Hanninen, R. W. Furst, A. Saalfrank, S. E. Ulbrich, J. Taponen, H. Lohi, E. Wolf, et al. (2012)
Biol Reprod 87, 140
   Abstract »    Full Text »    PDF »
NPSR1 Gene Is Associated with Reduced Risk of Rheumatoid Arthritis.
J Rheumatol 39, 1166-1170
   Abstract »    Full Text »    PDF »
Fine Mapping Study Reveals Novel Candidate Genes for Carotid Intima-Media Thickness in Dominican Republican Families.
L. Wang, A. Beecham, D. Zhuo, C. Dong, S. H. Blanton, T. Rundek, and R. L. Sacco (2012)
Circ Cardiovasc Genet 5, 234-241
   Abstract »    Full Text »    PDF »
Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.
D. P. B. McGovern, M. R. Jones, K. D. Taylor, K. Marciante, X. Yan, M. Dubinsky, A. Ippoliti, E. Vasiliauskas, D. Berel, C. Derkowski, et al. (2010)
Hum. Mol. Genet. 19, 3468-3476
   Abstract »    Full Text »    PDF »
Impact of genetic factors on lung development in health and disease.
P. LeSouef and M. Kabesch (2010)
Respiratory Diseases in Infants and Children 93-107
   Abstract »    Full Text »    PDF »
Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS).
F. Castro-Giner, R. de Cid, J. R. Gonzalez, D. Jarvis, J. Heinrich, C. Janson, E. R. Omenaas, M. C. Matheson, I. Pin, J. M. Anto, et al. (2010)
Thorax 65, 124-131
   Abstract »    Full Text »    PDF »
Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1.
U Huffmeier, J Lascorz, T Becker, F Schurmeier-Horst, A Magener, A B Ekici, S Endele, C T Thiel, S Thoma-Uszynski, R Mossner, et al. (2009)
J. Med. Genet. 46, 736-744
   Abstract »    Full Text »    PDF »
Positionally cloned asthma susceptibility gene polymorphisms and disease risk in the British 1958 Birth Cohort.
J D Blakey, I Sayers, S M Ring, D P Strachan, and I P Hall (2009)
Thorax 64, 381-387
   Abstract »    Full Text »    PDF »
Common polymorphic transcript variation in human disease.
H. B. Fraser and X. Xie (2009)
Genome Res. 19, 567-575
   Abstract »    Full Text »    PDF »
The protective effect of farm animal exposure on childhood allergy is modified by NPSR1 polymorphisms.
S Bruce, F Nyberg, E Melen, A James, V Pulkkinen, C Orsmark-Pietras, A Bergstrom, B Dahlen, M Wickman, E von Mutius, et al. (2009)
J. Med. Genet. 46, 159-167
   Abstract »    Full Text »    PDF »
In Vitro and in Vivo Pharmacological Characterization of the Neuropeptide S Receptor Antagonist [D-Cys(tBu)5]Neuropeptide S.
V. Camarda, A. Rizzi, C. Ruzza, S. Zucchini, G. Marzola, E. Marzola, R. Guerrini, S. Salvadori, R. K. Reinscheid, D. Regoli, et al. (2009)
J. Pharmacol. Exp. Ther. 328, 549-555
   Abstract »    Full Text »    PDF »
Dynamic variation in allele-specific gene expression of Paraoxonase-1 in murine and human tissues.
L. Parker-Katiraee, E. Bousiaki, D. Monk, G. E. Moore, K. Nakabayashi, and S. W. Scherer (2008)
Hum. Mol. Genet. 17, 3263-3270
   Abstract »    Full Text »    PDF »
Genetic testing for asthma.
G. H. Koppelman, G. J. te Meerman, and D. S. Postma (2008)
Eur. Respir. J. 32, 775-782
   Abstract »    Full Text »    PDF »
Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation.
J. H. White, M. Chiano, M. Wigglesworth, R. Geske, J. Riley, N. White, S. Hall, G. Zhu, F. Maurio, T. Savage, et al. (2008)
Hum. Mol. Genet. 17, 1890-1903
   Abstract »    Full Text »    PDF »
Biological and genetic interaction between Tenascin C and Neuropeptide S receptor 1 in allergic diseases.
C. Orsmark-Pietras, E. Melen, J. Vendelin, S. Bruce, A. Laitinen, L. A. Laitinen, R. Lauener, J. Riedler, E. von Mutius, G. Doekes, et al. (2008)
Hum. Mol. Genet. 17, 1673-1682
   Abstract »    Full Text »    PDF »
Synthesis and Pharmacological in Vitro and in Vivo Profile of 3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68), a Selective Antagonist of the Neuropeptide S Receptor.
N. Okamura, S. A. Habay, J. Zeng, A. R. Chamberlin, and R. K. Reinscheid (2008)
J. Pharmacol. Exp. Ther. 325, 893-901
   Abstract »    Full Text »    PDF »
A Roadmap to functional genomics.
R. B. Penn, V. E. Ortega, and E. R. Bleecker (2007)
Physiol Genomics 30, 82-88
   Abstract »    Full Text »    PDF »
A computational system to select candidate genes for complex human traits.
K. J. Gaulton, K. L. Mohlke, and T. J. Vision (2007)
Bioinformatics 23, 1132-1140
   Abstract »    Full Text »    PDF »
Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms.
S. T. Holgate, D. E. Davies, R. M. Powell, P. H. Howarth, H. M. Haitchi, and J. W. Holloway (2007)
Eur. Respir. J. 29, 793-803
   Abstract »    Full Text »    PDF »
Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica.
C. P Hersh, M. E Soto-Quiros, L. Avila, S. L Lake, C. Liang, E. Fournier, M. Spesny, J. S Sylvia, R. Lazarus, T. Hudson, et al. (2007)
Thorax 62, 224-230
   Abstract »    Full Text »    PDF »
Mammalian mRNA Splice-Isoform Selection Is Tightly Controlled.
J. L. Chisa and D. T. Burke (2007)
Genetics 175, 1079-1087
   Abstract »    Full Text »    PDF »
Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.
B. A. Raby, M. E. Soto-Quiros, L. Avila, S. L. Lake, A. Murphy, C. Liang, E. Fournier, M. Spesny, J. S. Sylvia, A. Verner, et al. (2007)
Hum. Mol. Genet. 16, 243-253
   Abstract »    Full Text »    PDF »
Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease.
I. C. Allen, A. J. Pace, L. A. Jania, J. G. Ledford, A. M. Latour, J. N. Snouwaert, V. Bernier, R. Stocco, A. G. Therien, and B. H. Koller (2006)
Am J Physiol Lung Cell Mol Physiol 291, L1005-L1017
   Abstract »    Full Text »    PDF »
Downstream target genes of the neuropeptide S-NPSR1 pathway.
J. Vendelin, S. Bruce, P. Holopainen, V. Pulkkinen, P. Rytila, A. Pirskanen, M. Rehn, T. Laitinen, L. A. Laitinen, T. Haahtela, et al. (2006)
Hum. Mol. Genet. 15, 2923-2935
   Abstract »    Full Text »    PDF »
Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene.
C Brasch-Andersen, Q Tan, A D Borglum, A Haagerup, T R Larsen, J Vestbo, and T A Kruse (2006)
Thorax 61, 874-879
   Abstract »    Full Text »    PDF »
Structure-Function Relationships in the Neuropeptide S Receptor: MOLECULAR CONSEQUENCES OF THE ASTHMA-ASSOCIATED MUTATION N107I.
V. Bernier, R. Stocco, M. J. Bogusky, J. G. Joyce, C. Parachoniak, K. Grenier, M. Arget, M.-C. Mathieu, G. P. O'Neill, D. Slipetz, et al. (2006)
J. Biol. Chem. 281, 24704-24712
   Abstract »    Full Text »    PDF »
A. L. Roth, E. Marzola, A. Rizzi, M. Arduin, C. Trapella, C. Corti, R. Vergura, P. Martinelli, S. Salvadori, D. Regoli, et al. (2006)
J. Biol. Chem. 281, 20809-20816
   Abstract »    Full Text »    PDF »
An empirical comparison of case-control and trio based study designs in high throughput association mapping.
P Hintsanen, P Sevon, P Onkamo, L Eronen, and H Toivonen (2006)
J. Med. Genet. 43, 617-624
   Abstract »    Full Text »    PDF »
Neuropeptide S and G protein-coupled receptor 154 modulate macrophage immune responses.
V. Pulkkinen, M.-L. Majuri, G. Wang, P. Holopainen, Y. Obase, J. Vendelin, H. Wolff, P. Rytila, L. A. Laitinen, T. Haahtela, et al. (2006)
Hum. Mol. Genet. 15, 1667-1679
   Abstract »    Full Text »    PDF »
Finding the molecular basis of complex genetic variation in humans and mice.
R. Mott (2006)
Phil Trans R Soc B 361, 393-401
   Abstract »    Full Text »    PDF »
Refinement of the 22q12-q13 Breast Cancer-Associated Region: Evidence of TMPRSS6 as a Candidate Gene in an Eastern Finnish Population.
J. M. Hartikainen, H. Tuhkanen, V. Kataja, M. Eskelinen, M. Uusitupa, V.-M. Kosma, and A. Mannermaa (2006)
Clin. Cancer Res. 12, 1454-1462
   Abstract »    Full Text »    PDF »
A Functional Variant in the Transcriptional Regulatory Region of Gene LOC344967 Cosegregates with Disease Phenotype in Familial Nasopharyngeal Carcinoma.
R.-C. Jiang, H.-D. Qin, M.-S. Zeng, W. Huang, B.-J. Feng, F. Zhang, H.-K. Chen, W.-H. Jia, L.-Z. Chen, Q.-S. Feng, et al. (2006)
Cancer Res. 66, 693-700
   Abstract »    Full Text »    PDF »
T-helper cell type-2 regulation in allergic disease.
S. N. Georas, J. Guo, U. De Fanis, and V. Casolaro (2005)
Eur. Respir. J. 26, 1119-1137
   Abstract »    Full Text »    PDF »
Pharmacological Characterization of Human and Murine Neuropeptide S Receptor Variants.
R. K. Reinscheid, Y.-L. Xu, N. Okamura, J. Zeng, S. Chung, R. Pai, Z. Wang, and O. Civelli (2005)
J. Pharmacol. Exp. Ther. 315, 1338-1345
   Abstract »    Full Text »    PDF »
Functional promoter SNPs in cell cycle checkpoint genes.
H. Belanger, P. Beaulieu, C. Moreau, D. Labuda, T. J. Hudson, and D. Sinnett (2005)
Hum. Mol. Genet. 14, 2641-2648
   Abstract »    Full Text »    PDF »
Mapping and identifying genes for asthma and psoriasis.
J. Kere (2005)
Phil Trans R Soc B 360, 1551-1561
   Abstract »    Full Text »    PDF »
Profile of Gene Expression in a Murine Model of Allergic Bronchopulmonary Aspergillosis.
V. P. Kurup, R. Raju, and P. Manickam (2005)
Infect. Immun. 73, 4381-4384
   Abstract »    Full Text »    PDF »
Is big beautiful? The continuing story of ADAM33 and asthma.
S T Holgate and J W Holloway (2005)
Thorax 60, 263-264
   Full Text »    PDF »
Interacting genetic loci cause airway hyperresponsiveness.
K. G. Ackerman, H. Huang, H. Grasemann, C. Puma, J. B. Singer, A. E. Hill, E. Lander, J. H. Nadeau, G. A. Churchill, J. M. Drazen, et al. (2005)
Physiol Genomics 21, 105-111
   Abstract »    Full Text »    PDF »
The landscape of genetic complexity across 5,700 gene expression traits in yeast.
R. B. Brem and L. Kruglyak (2005)
PNAS 102, 1572-1577
   Abstract »    Full Text »    PDF »
Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families.
E. Bouzigon, M.-H. Dizier, C. Krahenbuhl, A. Lemainque, I. Annesi-Maesano, C. Betard, J. Bousquet, D. Charpin, F. Gormand, M. Guilloud-Bataille, et al. (2004)
Hum. Mol. Genet. 13, 3103-3113
   Abstract »    Full Text »    PDF »
Sex specific protective effects of interleukin-9 receptor haplotypes on childhood wheezing and sensitisation.
E Melen, H Gullsten, M Zucchelli, A Lindstedt, F Nyberg, M Wickman, G Pershagen, and J Kere (2004)
J. Med. Genet. 41, e123
   Full Text »    PDF »
Human chromosome 7 circa 2004: a model for structural and functional studies of the human genome.
S. W. Scherer and E. D. Green (2004)
Hum. Mol. Genet. 13, R303-R313
   Abstract »    Full Text »    PDF »
Newly Discovered Asthma-Related Genes.
Journal Watch (General) 2004, 8
   Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882