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Nature 418, 426-430 (25 July 2002) | doi:10.1038/nature00878; Received 8 January 2002; Accepted 13 May 2002; Published online 10 July 2002

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Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Paul Van Eerdewegh1,2, Randall D. Little1,2, Josée Dupuis1,2, Richard G. Del Mastro1,2, Kathy Falls1, Jason Simon1,3, Dana Torrey1,3, Sunil Pandit1, Joyce McKenny1, Karen Braunschweiger1, Alison Walsh1, Ziying Liu1, Brooke Hayward1, Colleen Folz1,3, Susan P. Manning1, Alicia Bawa1, Lisa Saracino1, Michelle Thackston1, Youssef Benchekroun1, Neva Capparell1, Mei Wang1, Ron Adair1, Yun Feng1, JoAnn Dubois1, Michael G. FitzGerald1, Hui Huang1, René Gibson1, Kristina M. Allen1, Alex Pedan1, Melvyn R. Danzig4, Shelby P. Umland4, Robert W. Egan4, Francis M. Cuss4, Steuart Rorke5, Joanne B. Clough5, John W. Holloway5, Stephen T. Holgate5 & Tim P. Keith1

  1. Genome Therapeutics Corporation, 100 Beaver St, Waltham, Massachusetts 02453, USA
  2. Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, New Jersey 07033, USA
  3. Respiratory, Cell and Molecular Biology, Infection, Inflammation and Repair Research Division, School of Medicine, University of Southampton, Southampton General Hospital, Tremona Rd, Southampton, Hampshire, SO16 6YD, UK
  4. These authors contributed equally to the work
  5. Present addresses: Schering-Plough Research Institute, Kenilworth, New Jersey, USA, (J.S.); GPC Biotech AG, Cambridge, Massachusetts, USA, (D.T.); Biogen, Inc. Cambridge, Massachusetts, USA (C.F.)

Correspondence to: Tim P. Keith1 Correspondence and requests for materials should be addressed to T. K. (e-mail: Email: tkeith@genomecorp.com). Genbank accession numbers for the ADAM33 cDNAs are AF466287 and AF466289; the accession number for the genomic sequence is AF466288.

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Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component1, 2. To date, linkage studies have identified more than a dozen genomic regions linked to asthma3. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log10 of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene4 as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04–0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors5. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

  1. Genome Therapeutics Corporation, 100 Beaver St, Waltham, Massachusetts 02453, USA
  2. Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, New Jersey 07033, USA
  3. Respiratory, Cell and Molecular Biology, Infection, Inflammation and Repair Research Division, School of Medicine, University of Southampton, Southampton General Hospital, Tremona Rd, Southampton, Hampshire, SO16 6YD, UK
  4. These authors contributed equally to the work
  5. Present addresses: Schering-Plough Research Institute, Kenilworth, New Jersey, USA, (J.S.); GPC Biotech AG, Cambridge, Massachusetts, USA, (D.T.); Biogen, Inc. Cambridge, Massachusetts, USA (C.F.)

Correspondence to: Tim P. Keith1 Correspondence and requests for materials should be addressed to T. K. (e-mail: Email: tkeith@genomecorp.com). Genbank accession numbers for the ADAM33 cDNAs are AF466287 and AF466289; the accession number for the genomic sequence is AF466288.