Abstract
It is generally believed that an early age at the onset of disease is associated with a stronger genetic component. Our aim here was to investigate both linkage and genetic heterogeneity of asthma, the latter corresponding to different genotype relative risks of a putative linked gene according to age at onset of asthma. This analysis was conducted in 107 French EGEA families with at least two asthmatic siblings, considering 157 markers that were part of our previous genome screen, using the TTS (the Triangle Test Statistic) which has been developed to detect both linkage and intra-sibpair genetic heterogeneity. This test has been applied to 38 asthmatic sib-pairs discordant for age at the onset of asthma. To confirm the existence of genetic heterogeneity, we also used the predivided sample test (PST) which compares the IBD (identity by descent) distribution of marker alleles between asthmatic sib-pairs concordant (67) and discordant (38) for the age at onset. The cutoff point used for the age at onset was 4 years, the median age at onset in our sample of asthmatic sibs. Linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter) were indicated by both tests, TTS (P=0.005, P>0.5 after correction for multiple testing) and PST (P=0.0001, 0.015 after correction). These results suggest a genetic factor on 7q involved in asthma with genotype relative risks differing according to age at onset of disease.
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Ober C, Moffatt M . Contributing factors to the pathobiology : the genetics of asthma. In: Wenzel S (ed) The pathobiology of asthma WB Saunders, Philadelphia 2000 vol 21: p 245–261
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: 1 812–1818
Daniels SE, Bhattacharrya S, James A et al. WOC: A genome-wide search for quantitative trait loci underlying asthma Nature 1996 383: 247–250
The Collaborative Study on the Genetics of Asthma (CSGA) . A genome-wide search for asthma susceptibility loci in ethnically diverse populations Nature Genetics 1997 15: 389–392
Ober C, Cox NJ, Abney M et al. Genome-wide search for asthma susceptibility loci in a founder population Hum Mol Genet 1998 7: 1393–1398
Wjst M, Fisher G, Immervoll T et al. A genome-wide search for linkage to asthma Genomics 1999 58: 1–8
Kauffmann F, Becklake MR . Sex and gender In : Respiratory epidemiology in Europe. Annesi-Maesano I, Viegi G, Gulsvik A eds. Eur Respir Mon 2000 14: 288–304
Rackeman FM . A working classification of asthma Am J Med 1947 33: 601–606
Wenzel, S.E . Factors determining the severity of asthma Clin Exp Allergy 1998 28: suppl 5 119–125
Hall JM, Lee MK, Newman B et al. Linkage of early-onset familial breast cancer to chromosome 17q21 Science 1990 250: 1684–1689
Dizier MH, Quesneville H, Prum B, Selinger-Leneman H, Clerget-Darpoux F . The triangle test statistic (TTS) : a test of genetic homogeneity using the departure from the triangle constraints in IBD distribution among affected sib-pairs Ann Hum Genet 2000 64: 4 433–442
Kauffmann F, Dizier MH, Pin I et al. Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy (EGEA)-Phenotype issues Am J Respir Crit Care Med 1997 156: S123–S129
Kauffmann F, Dizier MH, Annesi-Maesano I et al. Etude épidémiologique des facteurs Génétiques et Environnementaux de l'Asthme, l'hyperréactivité bronchique et l'atopie (EGEA) - Protocole et biais de sélection potentiels. Rev Epidémiol Santé Pub in press
Oryszczyn M P, Annesi-Maesano I, Charpin D, Paty E, Maccario J, Kauffmann F . Relationships of active and passive smoking to total IgE in adults of EGEA – (Epidemiological study on the genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) Am J Respir Crit Care Med 2000 161: 1241–1246
Anonymous . 1993 United Medical and dental Schools of Guy's and St Thomas's Hospitals, Department of Public Health Medicine. Protocol for the European Community respiratory Health Survey. ISBN 1 869942 01 9 London
Risch N . Linkage strategies for genetically complex traits III. The effect of Marker polymorphism on analysis of affected relative pairs Am J Hum Genet 1990 46: 242–253
Suarez BK . The affected sib pair IBD distribution for HLA-linked disease susceptibility genes Tissue Antigens 1978 12: 87–93
Holmans P . Asymptotic properties of affected sib-pair linkage analysis Am J Hum Genet 1993 52: 362–374
Self SG, Liang KY . Asymptotic properties of maximum likelihood estimators and likelihood ratio tests under non-standard conditions J Am Stat Assoc 1987 82: 605–610
Morton NE . The detection and estimation of linkage between the genes for elliptocytosis and the Rh blood type Am J Hum Genet 1956 8: 80–96
Quesneville H, Dizier MH, Clerget-Darpoux F . Departure from the triangle constraints in discordant sib pairs: a test for genetic heterogeneity Genet Epidemiol 1999 17: 685–689
Hizawa N, Freidhoff LR, Chiu YF et al. Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: A genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs J Allergy Clin Immunol 1998 102: 436–442
Ober C, Tsalenko A, Willadsen S et al. Genome-wide screen for atopy susceptibility alleles in the Hutterites Clin Exp Allergy 1999 29: S11–S15
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
Wjst M. for the German asthma genetics group . Specific IgE-one gene fits all? Clin. Exp. Allergy 1999 29: S5–S10
Yokouchi Y, Nukaga Y, Shibasaki M et al. Significant evidence for linkage of mite-sensitive childhood to chromosome 5q31-q33 near the interleukin 12B locus by a genome-wide search in Japanese families Genomics 2000 66: 152–160
Xu J, Postma DS, Howard TD et al. Major genes regulating total serum immunoglobulin E levels in families with asthma Am J Hum Genet 2000 67: 1163–1173
Dahl M, Tyaer-Hansen A, Lange P, Nordestgaard BG . ΔF508 heterozygosity in cystic fibrosis and susceptibility to asthma Lancet 1998 351: 1911–1912
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
De Cid R, Chomel JC, Lazaro C et al. CFTR and asthma in the French EGEA study Eur J Hum Gen 2001 9: 67–69
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This work was supported by convention INSERM-MSD, INSERM networks of clinical research (489012) and public health research (493009) and INSERM grant (IDS-4D006D). Kits for IgE and Phadiatop determinations were kindly provided by Pharmacia.
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Dizier, MH., Besse-Schmittler, C., Guilloud-Bataille, M. et al. Indication of linkage and genetic heterogeneity of asthma according to age at onset on chromosome 7q in 107 French EGEA families. Eur J Hum Genet 9, 867–872 (2001). https://doi.org/10.1038/sj.ejhg.5200732
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DOI: https://doi.org/10.1038/sj.ejhg.5200732
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