Abstract
Non-specific bronchial hyper-responsiveness to various inhaled stimuli is a characteristic of asthma. We have previously shown linkage of bronchial responsiveness to methacholine (measured as dose-response slope (DRS)) and the peripheral blood eosinophil count (EOS) to chromosome 7. We have now further investigated these linkages by genotyping 49 microsatellite markers across the DRS locus on chromosome 7. The markers were spaced on average 2.6 cM apart and spanned a sex averaged cumulative genetic distance of 129 cM. Multipoint linkage to DRS was bimodal and dipped at the centromere. The two peaks of linkage were close to markers D7S484 (P=0.0003) and D7S669 (P=0.006) respectively. Separate testing for linkage to paternally and maternally derived alleles showed that the linkage near D7S484 was paternally derived (P<0.00001): maternally derived alleles did not exhibit significant linkage. The results indicate that two disparate loci may be influencing asthma from chromosome 7.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Cookson W . The alliance of genes and environment in asthma and allergy Nature 1999 402: B5–11
Holberg CJ, Elston RC, Halonen M et al. Segregation analysis of physician-diagnosed asthma in Hispanic and non- Hispanic white families. A recessive component? Am J Respir Crit Care Med 1996 54: 144–150
Sandford A, Weir T, Pare P . The genetics of asthma Am J Respir Crit Care Med 1996 153: 1749–1765
Britton J . Is hyperreactivity the same as asthma? Eur Respir J 1988 1: 478–479
Townley RG, Bewtra A, Wilson AF et al. Segregation analysis of bronchial response to methacholine inhalation challenge in families with and without asthma J Allergy Clin Immunol 1986 77: 101–107
Palmer LJ, Burton PR, Faux JA et al. Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness Am J Respir Crit Care Med 2000 161: 1836–1843
Turki J, Pak J, Green SA, Martin RJ, Liggett SB . Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype J Clin Invest 1995 95: 1635–1641
Daniels SE, Bhattacharrya S, James A et al. A genome-wide search for quantitative trait loci underlying asthma Nature 1996 383: 247–250
Hill MR, Cookson WOCM . A new variant of the β subunit of the high affinity receptor for Immunoglobulin E (FcεRI-E237G): associations with measures of atopy and bronchial hyper-responsiveness Human Molecular Genetics 1996 5: 959–962
De Sanctis GT, Merchant M, Beier DR et al. Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice Nat Genet 1995 11: 150–154
Zhang Y, Lefort J, Kearsey V et al. A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma Hum Mol Genet 1999 8: 601–605
Dizier MH, Besse-Schmittler C, Guilloud-Bataille M et al. Genome screen for asthma and related phenotypes in the French EGEA study Am J Respir Crit Care Med 2000 162: 1812–1818
Wjst M, Fischer G, Immervoll T et al. A genome-wide search for linkage to asthma. German Asthma Genetics Group Genomics 1999 58: 1–8
Ober C, Tsalenko A, Parry R, Cox NJ . A second-generation genomewide screen for asthma-susceptibility alleles in a founder population Am J Hum Genet 2000 67: 1154–1162
Laitinen T, Daly MJ, Rioux JD et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population Nat Genet 2001 28: 87–91
Satsangi J, Parkes M, Louis E et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12 Nat Genet 1996 14: 199–202
Becker K, Simon R, Bailey-Wilson J et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases Proc Natl Acad Sci USA 1998 95: 9979–9984
Yan K, Salome C, Woolcock AJ . Rapid method for measurement of bronchial responsiveness Thorax 1983 38: 760–765
Hill MR, James AL, Faux JA et al. Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample BMJ 1995 311: 776–779
Cookson WOCM, De Klerk NH, Ryan GR, James AL, Musk AW . Relative risks of bronchial hyper-responsiveness associated with skin-prick test responses to common antigens in young adults Clin Exp Allergy 1991 21: 473–479
Dib C, Faure S, Fizames C et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites Nature 1996 380: 152–154
Reed PW, Davies JL, Copeman JB et al. Chromosome-specific microsatellite sets for fluorescence-based, semi- automated genome mapping Nat Genet 1994 7: 390–395
SAGE. Statistical analysis for genetic epidemiology. Computer program package available from the Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA 1997
Terwilliger JD, Weiss KM . Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biotechnol 1998 9: 578–594
Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination Am J Hum Genet 1998 63: 861–869
Morison IM, Reeve AE . A catalogue of imprinted genes and parent-of-origin effects in humans and animals Hum Mol Genet 1998 7: 1599–1609
Moffatt M, Cookson W . The genetics of asthma. Maternal effects in atopic disease Clin Exp Allergy 1998 28 1: 56–61 discussion 65–66
Fazio MJ, Mattei MG, Passage E et al. Human elastin gene: new evidence for localization to the long arm of chromosome 7 Am J Hum Genet 1991 48: 696–703
Pare PD, Roberts CR, Bai TR, Wiggs BJ . The functional consequences of airway remodeling in asthma Monaldi Arch Chest Dis 1997 52: 589–596
Bousquet J, Lacoste JY, Chanez P et al. Bronchial elastic fibers in normal subjects and asthmatic patients Am J Respir Crit Care Med 1996 153: 1648–1654
McCarthy DS, Sigurdson M . Lung elastic recoil and reduced airflow in clinically stable asthma Thorax 1980 35: 298–302
Ota N, Hunt SC, Nakajima T et al. Linkage of interleukin 6 locus to human osteopenia by sibling pair analysis Hum Genet 1999 105: 253–257
Fishman D, Faulds G, Jeffery R et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis J Clin Invest 1998 102: 1369–1376
Yokoyama A, Kohno N, Fujino S et al. Circulating interleukin-6 levels in patients with bronchial asthma Am J Respir Crit Care Med 1995 151: 1354–1358
DiCosmo B, Geba G, Picarella D et al. Expression of interleukin-6 by airway epithelial cells. Effects on airway inflammation and hyperreactivity in transgenic mice Chest 1995 107: 131S
Kurz T, Strauch K, Heinzmann A et al. A European study on the genetics of mite sensitization J Allergy Clin Immunol 2000 106: 925–932
Lazaro C, de Cid R, Sunyer J et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma Hum Mutat 1999 14: 510–519
Acknowledgements
The Wellcome Trust funded this work. We thank the Busselton families and all those who have helped study them. Some of the results of this paper were obtained by using the program package S.A.G.E., which is supported by a U.S. Public Health Services Resource Grant (1 P41 RR03655) from the National Centre for Research Resources.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Leaves, N., Bhattacharyya, S., Wiltshire, S. et al. A detailed genetic map of the chromosome 7 bronchial hyper-responsiveness locus. Eur J Hum Genet 10, 177–182 (2002). https://doi.org/10.1038/sj.ejhg.5200787
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200787