A Sandford, T Weir and P Pare
The University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada.

In this paper we have summarized the evidence for a genetic contribution to asthma as well as the recent advances in techniques for identifying the location and function of genes that cause complex diseases. We have also reviewed how these techniques have been applied to the study of asthma and allergy. It is likely that rapid additional advances will be made over the next several years. There are ongoing genome-wide searches to identify additional genes. An understanding of the genetic variation that predisposes people to asthma and the atopic diseases could open a variety of potential diagnostic and therapeutic avenues. Firstly, the identification of the specific mutations that alter the immune response could provide targets for gene therapy. However, in the short run this is unlikely because the risks and costs associated with gene therapy do not presently justify application to alleviate the relatively nonlethal manifestations of allergic diseases. The second potential avenue will be in the development of specific pharmacologic therapy. For example, if variants of the IL-4 gene with enhanced function or of the IFN-gamma gene that have deficient function are identified as causative factors, drug development could be directed toward specific modulators of their effects. However, it is possible that redundancy in the immune and inflammatory responses, coupled with the likelihood of multiple gene involvement, will make such targeting fruitless or dangerous. The third consequence of identifying genetic variants predisposing to asthma and allergy is the possibility of screening. This is perhaps the most likely beneficial outcome of the present search for atopy genes. Recent studies suggest that the clinical onset of atopic diseases can be modified by preventing exposure to cigarette smoke and highly allergenic proteins in the first few years of life (188). At present the power of such studies is limited by the inability to predict those at risk with any certainty. Genetic screening of children born to atopic parents will allow more precise identification of those carrying atopy genes, and this could allow a focused attempt at environmental modification. In the short run this will allow the design of much more powerful prospective studies of prophylaxis, and in the long run screening may prove an effective strategy for asthma prevention.

This article has been cited by other articles:

				Y.-L. Lee, T.-R. Hsiue, Y.-C. Lee, Y.-C. Lin, and Y. L. Guo The Association Between Glutathione S-Transferase P1, M1 Polymorphisms and Asthma in Taiwanese Schoolchildren Chest, September 1, 2005; 128(3): 1156 - 1162. [Abstract] [Full Text] [PDF]

				D. A. Schwartz, J. H. Freedman, and E. A. Linney Environmental genomics: a key to understanding biology, pathophysiology and disease Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R217 - R224. [Abstract] [Full Text] [PDF]

				E. Paraskakis, G. Sourvinos, F. Passam, N. Tzanakis, E.G. Tzortzaki, M. Zervou, D. Spandidos, and N.M. Siafakas Microsatellite DNA instability and loss of heterozygosity in bronchial asthma Eur. Respir. J., December 1, 2003; 22(6): 951 - 955. [Abstract] [Full Text] [PDF]

				E. D. Boudreaux, S. D. Emond, S. Clark, and C. A. Camargo Jr Acute Asthma Among Adults Presenting to the Emergency Department: The Role of Race/Ethnicity and Socioeconomic Status Chest, September 1, 2003; 124(3): 803 - 812. [Abstract] [Full Text] [PDF]

				G. S. Whitehead, J. K. L. Walker, K. G. Berman, W. M. Foster, and D. A. Schwartz Allergen-induced airway disease is mouse strain dependent Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L32 - L42. [Abstract] [Full Text] [PDF]

				M. B. Bracken, K. Belanger, W. O. Cookson, E. Triche, D. C. Christiani, and B. P. Leaderer Genetic and Perinatal Risk Factors for Asthma Onset and Severity: A Review and Theoretical Analysis Epidemiol. Rev., December 1, 2002; 24(2): 176 - 189. [Full Text] [PDF]

				T. Aoki-Nagase, T. Nagase, Y. Oh-hashi, T. Shindo, Y. Kurihara, Y. Yamaguchi, H. Yamamoto, T. Tomita, E. Ohga, R. Nagai, et al. Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L963 - L970. [Abstract] [Full Text] [PDF]

				M. N. Hylkema, W. Timens, M. Luinge, N. van der Werf, and M. O. Hoekstra The Effect of Bacillus Calmette-Guerin Immunization Depends on the Genetic Predisposition to Th2-Type Responsiveness Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 244 - 249. [Abstract] [Full Text] [PDF]

				C. K. Haston, X. Zhou, L. Gumbiner-Russo, R. Irani, R. Dejournett, X. Gu, M. Weil, C. I. Amos, and E. L. Travis Universal and Radiation-specific Loci Influence Murine Susceptibility to Radiation-induced Pulmonary Fibrosis Cancer Res., July 1, 2002; 62(13): 3782 - 3788. [Abstract] [Full Text] [PDF]

				T. NAGASE, S. ISHII, H. SHINDOU, Y. OUCHI, and T. SHIMIZU Airway Hyperresponsiveness in Transgenic Mice Overexpressing Platelet Activating Factor Receptor Is Mediated by an Atropine-Sensitive Pathway Am. J. Respir. Crit. Care Med., January 15, 2002; 165(2): 200 - 205. [Abstract] [Full Text] [PDF]

				J. C. Celedon, M. E. Soto-Quiros, E. K. Silverman, L. A. Hanson, and S. T. Weiss Risk Factors For Childhood Asthma in Costa Rica Chest, September 1, 2001; 120(3): 785 - 790. [Abstract] [Full Text] [PDF]

				K G Tantisira and S T Weiss Complex interactions in complex traits: obesity and asthma Thorax, September 1, 2001; 56(90002): ii64 - 74. [Full Text] [PDF]

				Z. WANG, C. CHEN, T. NIU, D. WU, J. YANG, B. WANG, Z. FANG, C. N. YANDAVA, J. M. DRAZEN, S. T. WEISS, et al. Association of Asthma with {beta}2-Adrenergic Receptor Gene Polymorphism and Cigarette Smoking Am. J. Respir. Crit. Care Med., May 1, 2001; 163(6): 1404 - 1409. [Abstract] [Full Text]

				L.J. Palmer, M.W. Knuiman, M.L. Divitini, P.R. Burton, A.L. James, H.C. Bartholomew, G. Ryan, and A.W. Musk Familial aggregation and heritability of adult lung function: results from the Busselton Health Study Eur. Respir. J., April 1, 2001; 17(4): 696 - 702. [Abstract] [Full Text] [PDF]

				L. J. PALMER, P. J. RYE, N. A. GIBSON, P. R. BURTON, L. I. LANDAU, and P. N. LESOUËF Airway Responsiveness in Early Infancy Predicts Asthma, Lung Function, and Respiratory Symptoms by School Age Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 37 - 42. [Abstract] [Full Text]

				C. ANDREW ALIGNE, P. AUINGER, R. S. BYRD, and M. WEITZMAN Risk Factors for Pediatric Asthma . Contributions of Poverty, Race, and Urban Residence Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 873 - 877. [Abstract] [Full Text]

				L. J. Palmer and W. O.C.M. Cookson Genomic Approaches to Understanding Asthma Genome Res., September 1, 2000; 10(9): 1280 - 1287. [Abstract] [Full Text]

				J. L. L. KIMPEN Viral Infections and Childhood Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S108 - 112. [Full Text] [PDF]

				E. K. Silverman and L. J. Palmer Case-Control Association Studies for the Genetics of Complex Respiratory Diseases Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 645 - 648. [Full Text]

				S. ZHU, M. CHAN-YEUNG, A. B. BECKER, H. DIMICH-WARD, A. C. FERGUSON, J. MANFREDA, W. T. A. WATSON, P. D. PARÉ, and A. J. SANDFORD Polymorphisms of the IL-4, TNF-alpha , and Fcalpha RIbeta Genes and the Risk of Allergic Disorders in At-risk Infants Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1655 - 1659. [Abstract] [Full Text]

				T. Nagase, H. Kurihara, Y. Kurihara, T. Aoki-Nagase, R. Nagai, and Y. Ouchi Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice J Appl Physiol, December 1, 1999; 87(6): 2020 - 2024. [Abstract] [Full Text] [PDF]

				C. A. Camargo Jr, S. T. Weiss, S. Zhang, W. C. Willett, and F. E. Speizer Prospective Study of Body Mass Index, Weight Change, and Risk of Adult-onset Asthma in Women Arch Intern Med, November 22, 1999; 159(21): 2582 - 2588. [Abstract] [Full Text] [PDF]

				J. P. BREWER, A. B. KISSELGOF, and T. R. MARTIN Genetic Variability in Pulmonary Physiological, Cellular, and Antibody Responses to Antigen in Mice Am. J. Respir. Crit. Care Med., October 1, 1999; 160(4): 1150 - 1156. [Abstract] [Full Text]

				A. J. NEWMAN TAYLOR, P. CULLINAN, P. A. LYMPANY, J. M. HARRIS, R. J. DOWDESWELL, and R. M. du BOIS Interaction of HLA Phenotype and Exposure Intensity in Sensitization to Complex Platinum Salts Am. J. Respir. Crit. Care Med., August 1, 1999; 160(2): 435 - 438. [Abstract] [Full Text]

				M. HALONEN, D. A. STERN, C. LOHMAN, A. L. WRIGHT, M. A. BROWN, and F. D. MARTINEZ Two Subphenotypes of Childhood Asthma That Differ in Maternal and Paternal Influences on Asthma Risk Am. J. Respir. Crit. Care Med., August 1, 1999; 160(2): 564 - 570. [Abstract] [Full Text]

				N. R LYNCH, J GOLDBLATT, and P N LE SOUËF Parasite infections and the risk of asthma and atopy Thorax, August 1, 1999; 54(8): 659 - 660. [Full Text]

				T. CHAGANI, P. D. PARÉ, S. ZHU, T. D. WEIR, T. R. BAI, N. A. BEHBEHANI, kJ. M. FITZGERALD, and A. J. SANDFORD Prevalence of Tumor Necrosis Factor-alpha and Angiotensin Converting Enzyme Polymorphisms in Mild/Moderate and Fatal/Near-Fatal Asthma Am. J. Respir. Crit. Care Med., July 1, 1999; 160(1): 278 - 282. [Abstract] [Full Text]

				Y. ARON, B. S. POLLA, T. BIENVENU, J. DALL'AVA, D. DUSSER, and D. HUBERT HLA Class II Polymorphism in Cystic Fibrosis . A Possible Modifier of Pulmonary Phenotype Am. J. Respir. Crit. Care Med., May 1, 1999; 159(5): 1464 - 1468. [Abstract] [Full Text] [PDF]

				S. Rieger, H. Riemer, and C. Mannhalter Multiplex PCR Assay for the Detection of Genetic Variants of {alpha}1-Antitrypsin Clin. Chem., May 1, 1999; 45(5): 688 - 690. [Full Text] [PDF]

				K. A Deichmann, B. Starke, S. Schlenther, A. Heinzmann, S. H. Sparholt, J. Forster, and J. Kuehr Linkage and association studies of atopy and the chromosome 11q13 region J. Med. Genet., May 1, 1999; 36(5): 379 - 382. [Abstract] [Full Text]

				P. J Barnes Genetics and pulmonary medicine bullet  9: Molecular genetics of chronic obstructive pulmonary disease Thorax, March 1, 1999; 54(3): 245 - 252. [Full Text]

				I P Hall Genetics and pulmonary medicine bullet  8: Genetics and pulmonary medicine: asthma Thorax, January 1, 1999; 54(1): 65 - 69. [Full Text]

				G. Grünig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, et al. Requirement for IL-13 Independently of IL-4 in Experimental Asthma Science, December 18, 1998; 282(5397): 2261 - 2263. [Abstract] [Full Text]

				F. D. MARTINEZ, S. SOLOMON, C. J. HOLBERG, P. E. GRAVES, M. BALDINI, and R. P. ERICKSON Linkage of Circulating Eosinophils to Markers on Chromosome 5q Am. J. Respir. Crit. Care Med., December 1, 1998; 158(6): 1739 - 1744. [Abstract] [Full Text] [PDF]

				L. J. PALMER, S. E. DANIELS, P. J. RYE, N. A. GIBSON, G. K. TAY, W. O. C. M. COOKSON, J. GOLDBLATT, P. R. BURTON, and P. N. LESOUEF Linkage of Chromosome 5q and 11q Gene Markers to Asthma-associated Quantitative Traits in Australian Children Am. J. Respir. Crit. Care Med., December 1, 1998; 158(6): 1825 - 1830. [Abstract] [Full Text] [PDF]

				G G Anderson and J F J Morrison Molecular biology and genetics of allergy and asthma Arch. Dis. Child., May 1, 1998; 78(5): 488 - 496. [Full Text]

				J. A. NADEL and W. W. BUSSE Asthma Am. J. Respir. Crit. Care Med., April 1, 1998; 157(4): S130 - S138. [Full Text] [PDF]

				Genes for asthma? An analysis of the European Community Respiratory Health Survey Am. J. Respir. Crit. Care Med., December 1, 1997; 156(6): 1773 - 1780. [Abstract] [Full Text]

				E Lombardi, W. Morgan, A. Wright, R. Stein, C. Holberg, and F. Martinez Cold air challenge at age 6 and subsequent incidence of asthma. A longitudinal study Am. J. Respir. Crit. Care Med., December 1, 1997; 156(6): 1863 - 1869. [Abstract] [Full Text]

				T. NAGASE, S. ISHII, H. KATAYAMA, Y. FUKUCHI, Y. OUCHI, and T. SHIMIZU Airway Responsiveness in Transgenic Mice Overexpressing Platelet-activating Factor Receptor . Roles of Thromboxanes and Leukotrienes Am. J. Respir. Crit. Care Med., November 1, 1997; 156(5): 1621 - 1627. [Abstract] [Full Text]

				E. R. BLEECKER, D. S. POSTMA, and D. A. MEYERS Evidence for Multiple Genetic Susceptibility Loci for Asthma Am. J. Respir. Crit. Care Med., October 1, 1997; 156(4): S113 - S116. [Abstract] [Full Text] [PDF]

				C. E. MAPP, A. BALBONI, R. BARICORDI, and L. M. FABBRI Human Leukocyte Antigen Associations in Occupational Asthma Induced by Isocyanates Am. J. Respir. Crit. Care Med., October 1, 1997; 156(4): S139 - S143. [Abstract] [Full Text] [PDF]

				N. S. THOMAS, J. WILKINSON, and S. T. HOLGATE The Candidate Region Approach to the Genetics of Asthma and Allergy Am. J. Respir. Crit. Care Med., October 1, 1997; 156(4): S144 - S151. [Abstract] [Full Text] [PDF]

				T. NAGASE, H. KURIHARA, Y. KURIHARA, T. AOKI, Y. FUKUCHI, Y. YAZAKI, and Y. OUCHI Airway Hyperresponsiveness to Methacholine in Mutant Mice Deficient in Endothelin-1 Am. J. Respir. Crit. Care Med., February 1, 1997; 157(2): 560 - 564. [Abstract] [Full Text]