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Novel association suggests multiple independent QTLs within chromosome 5q21–33 region control variation in total humans IgE levels

Genes & Immunity volume 4, pages 289–297 (2003)Cite this article

Abstract

Asthma is a common, heterogeneous, complex disease accompanied by raised total and specific immunoglobulin-E (IgE) antibody levels. Despite numerous previous reports of linkage and association of asthma, atopy and serum IgE levels to genes within the 5q21–33 region, definitive, replicable results are still not available. We used the classical twin design to (i) estimate the relative contributions of genes and environment to variation in total IgE levels, (ii) assess genetic linkage, and (iii) examine allelic association of 11 microsatellite markers spanning the 5q21–33 region to total IgE. Variation in total IgE level was shown to be highly heritable (65%). Although evidence for linkage of the 11 microsatellites to IgE was not observed, the omnibus test of association, not confounded by population substructure, showed positive association of D5S393 and D5S673 to IgE. Genes in the vicinity of D5S673 include hepatitis A virus receptor (HAVCR-1) and IL-12B. Recently, the mouse orthologue of HAVCR-1, the T-cell membrane family of proteins, have been shown to be in strong association with expression of airway hyperactivity in a mouse model of human asthma and atopy. IL-12B subserves many proinflammatory functions and also induces B cells proliferation.

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References

  1. Holgate ST, Corne J, Jardieu P, Fick RB, Heusser CH . 30 years with IgE. Munksgaard: Copenhagen, 1998.

    Google Scholar 

  2. Kon OM, Sihra BS, Compton CH, Leonard TB, Kay AB, Barnes NC . Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet 1998; 352: 1109–1113.

    Article  CAS  PubMed  Google Scholar 

  3. Martinez FD . Complexities of the genetics of asthma. Am J Respir Crit Care Med 1997; 156 (4) (Part 2): S117–S122.

    Article  CAS  PubMed  Google Scholar 

  4. Nadeau JH, Frankel WN . The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat Genet 2000; 25: 381–384.

    Article  CAS  PubMed  Google Scholar 

  5. Stoll M, Cowley Jr AW, Tonellato PJ et al. A genomic-systems biology map for cardiovascular function. Science 2001; 294: 1723–1726.

    Article  CAS  PubMed  Google Scholar 

  6. Silverman EK, Mosley JD, Rao DC et al. Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases. Hum Heredity 2001; 52: 223–232.

    Article  CAS  PubMed  Google Scholar 

  7. Schork NJ . Genetics of complex disease: approaches, problems, and solutions [Review]. Am J Respir Crit Care Med 1997; 156(4 Part 2): S103–S109.

    Article  CAS  PubMed  Google Scholar 

  8. Martin N, Boomsma D, Machin G . A twin-pronged attack on complex traits [Review]. Nat Gene 1997; 17: 387–392.

    Article  CAS  Google Scholar 

  9. Ahmadi KR, Hall MA, Norman PJ et al. Genetic determinism in the relationship between human CD4+ and CD8+ T lymphocyte populations? Genes Immun 2001; 2: 381–387.

    Article  CAS  PubMed  Google Scholar 

  10. Jones CA, Kilburn SA, Warner JA, Warner JO . Intrauterine environment and fetal allergic sensitization. Clin Exp Allergy 1998; 28: 655–659.

    Article  CAS  PubMed  Google Scholar 

  11. Abecasis GR, Cherny SS, Cardon LR . The impact of genotyping error on family-based analysis of quantitative traits. Eur J Hum Gene 2001; 9: 130–134.

    Article  CAS  Google Scholar 

  12. Matricardi PM . Infections preventing atopy: facts and new questions. Allergy 1997; 52: 879–882.

    Article  CAS  PubMed  Google Scholar 

  13. Strachan DP . Lifestyle and atopy. Lancet 1999; 353: 1457–1458.

    Article  CAS  PubMed  Google Scholar 

  14. Lonjou C, Barnes KC, Chen H et al. A first trial of retrospective collaboration for positional cloning in complex inheritance: assay of the cytokine region in chromosome 5 by the consortium on asthma genetics (COAG). Proc Natl Acad Sci USA 2000; 97: 10942–10947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Palmer LJ, Barnes KC, Burton PR et al. Meta-analysis for linkage to asthma and atopy in the chromosome 5q31–33 candidate region. Hum Mol Genet 2001; 10: 891–899.

    Article  CAS  PubMed  Google Scholar 

  16. Moffatt MF, Hill MR, Schou C et al. Genetic linkage of T-cell receptor α/δ complex to specific IgE responses. Lancet 1994; 343: 1597–1600.

    Article  CAS  PubMed  Google Scholar 

  17. Daniels SE, Bhattacharrya S, James A et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 1996; 383: 247–250.

    Article  CAS  PubMed  Google Scholar 

  18. Barnes KC, Neely JD, Duffy DL et al. Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations. Genomics 1996; 37: 41–50.

    Article  CAS  PubMed  Google Scholar 

  19. Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S . Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol 1996; 97: 1288–1296.

    Article  CAS  PubMed  Google Scholar 

  20. Sandford A, Weir T, Pare P . The genetics of asthma. Am J Respir Crit Care Med 1996; 153: 1749–1765.

    Article  CAS  PubMed  Google Scholar 

  21. CSGA. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet 1997; 15: 389–392.

  22. Palmer LJ, Pare PD, Faux JA et al. Fc epsilon R1-beta polymorphism and total serum IgE levels in endemically parasitized Australian aborigines. Am J Hum Genet 1997; 61: 182–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Thomas NS, Wilkinson J, Holgate ST . The candidate region approach to the genetics of asthma and allergy. Am J Respir Crit Care Med 1997; 156 (4 Part 2): S144–S151.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ober C, Leavitt SA, Tsalenko A et al. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 2000; 66: 517–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Laitinen T, Daly MJ, Rioux JD et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scans in a founder population. Nat Genet 2001; 28: 87–91.

    CAS  PubMed  Google Scholar 

  28. Cookson WOC, Ubhi B, Lawrence R et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001; 27: 372–373.

    Article  CAS  PubMed  Google Scholar 

  29. Hastbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E . Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland (published erratum appears in Nat Genet 1992; 2: 343). Nat Genet 1992; 2: 204–211.

    Article  CAS  PubMed  Google Scholar 

  30. Jabs EW, Li X, Lovett M et al. Genetic and physical mapping of the Treacher Collins Syndrome locus with respect to loci in the chromosome 5q31 region. Genomics 1993; 18: 7–13.

    Article  CAS  PubMed  Google Scholar 

  31. Rihet P, Traore Y, Abel L, Aucan C, Traore-Leroux T, Fumoux F . Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31–q33. Am J Hum Genet 1998; 63: 498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rioux JD, Stone VA, Daly MJ et al Familial eosinophelia maps to the cytokine gene cluster on human chromosomal region 5q31–33. Am J Hum Genet 1998; 63: 1086–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chavanas S, Garner C, Bodemer C et al. Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygocity mapping. Am J Hum Genet 2000; 66: 914–921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rioux JD, Daly MJ, Silverberg MS et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.

    Article  CAS  PubMed  Google Scholar 

  35. Skadhauge LR, Christensen K, Kyvik KO, Sigsgaard T . Genetic and environmental influence on asthma: a population-based study of 11,688 Danish twin pairs. Eur Respir J 1999; 13: 8–14.

    Article  CAS  PubMed  Google Scholar 

  36. Bosken CH, Ko YC, Shete S et al. Adaptations of linkage and association methods for the study of asthma, a complex trait. Genet Epidemiol 2001; 21 (Suppl 1): S89–S96.

    Article  PubMed  Google Scholar 

  37. Meyers DA, Postma DS, Panhuysen CI et al. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 1994; 23: 464–470.

    Article  CAS  PubMed  Google Scholar 

  38. Marsh DG, Neely JD, Breazeale DR et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994; 264: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  39. Gao PS, Mao XQ, Baldini M et al. Serum total IgE levels and CD14 on chromosome 5q31 [letter]. Clin Genet 1999; 56: 164–165.

    Article  CAS  PubMed  Google Scholar 

  40. Walley AJ, Wiltshire S, Ellis CM, Cookson WO . Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits. Genomics 2001; 72:15–20.

    Article  CAS  PubMed  Google Scholar 

  41. McIntire JJ, Umetsu SE, Akbari O et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2001; 2: 1109–1116.

    Article  CAS  PubMed  Google Scholar 

  42. Mathias RA, Freidhoff LR, Blumenthal M et al. Genomewide linkage analyses of total serum IgE using variance components analysis in asthmatic families. Genet Epidemiol 2001; 20: 340–355.

    Article  CAS  PubMed  Google Scholar 

  43. Philips DIW . Fetal programming or genes? In: Spector TD, Snieder H, MacGregor AJ (eds). Advances in Twin and Sib-pair Analysis. Oxford University Press: Oxford, 2000: pp. 79–89.

    Google Scholar 

  44. Shah A . Asthma and sex. Indian J Chest Dis Allied Sci 2001; 43: 135–137.

    CAS  PubMed  Google Scholar 

  45. Fagan JK, Scheff PA, Hryhorczuk D, Ramakrishnan V, Ross M, Perskey V . Prevalence of asthma and other allergic diseases in an adolescent population:association with gender and race. Ann Allergy Asthma Immunol 2001; 86: 177–184.

    Article  CAS  PubMed  Google Scholar 

  46. Bjornson CL, Mitchell I . Gender differences in asthma in childhood and adolescence. J Gender Specific Med 2000; 3: 57–61.

    CAS  Google Scholar 

  47. Muller-Myhsok B, Abel L . Genetic analysis of complex diseases. Science 1998; 275: 1328–1329.

    Google Scholar 

  48. Kruglyak L . Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 1999; 22: 139–144.

    Article  CAS  PubMed  Google Scholar 

  49. Cardon LR, Abecasis GR . Some properties of a variance components model for fine-mapping quantitative trait loci. Behav Genet 2000; 30: 235–243.

    Article  CAS  PubMed  Google Scholar 

  50. Ahmadi KR, Hall MA, Norman PJ, Vaughan RW, Spector TD, Lanchbury JS . A simple genotype-quantitative phenotype relationship in humans: a case study of T cell receptor Vβ6.7. Am J Hum Genet 69 (4), 1312, 2001.

    Google Scholar 

  51. Collins A, Lonjou C, Morton NE . Genetic epidemiology of single-nucleotide polymorphisms. Proc Nat Acad Sci USA 1999; 96: 15 173–15 177.

    Article  CAS  Google Scholar 

  52. Reich DE, Cargill M, Bolk S et al. Linkage disequilibrium in the human genome. Nature 2001; 411: 199–204.

    Article  CAS  PubMed  Google Scholar 

  53. Laan M, Pääbo S . Demographic history and linkage disequilibrium in human populations. Nat Genet 1997; 17:435–438.

    Article  CAS  PubMed  Google Scholar 

  54. Thompson EA, Neel JV . Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. Am J Hum Genet 1997; 60: 197–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Harpending H, Rogers A . Genetic perspectives on human origins and differentiation. Annu Rev Genom Hum Genet 2000; 1: 361–385.

    Article  CAS  Google Scholar 

  56. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES . High resolution haplotype structure in the human genome. Nat Genet 2001; 29: 229–232.

    Article  CAS  PubMed  Google Scholar 

  57. Andrew T, Hart DJ, Snieder H, de Lange M, Spector TD, MacGregor AJ . Are twins and singletons comparable? A study of disease-related and life-style characteristics in adult woman. Twin Res 2001; 4: 464–477.

    Article  CAS  PubMed  Google Scholar 

  58. Goldsmith HH . A zygosity questionnaire for young twins: a research note. Behav Genet 1991; 21: 257–269.

    Article  CAS  PubMed  Google Scholar 

  59. Reed PW, Davis JL, Copeman JB et al. Chromosome-specific microsatellite sets for flourescence-based, semi-automated genome mapping. Nat Genet 1994; 7: 343–344.

    Article  Google Scholar 

  60. Pritchard LE, Kawaguchi Y, Reed PW et al. Analysis of the CD3 gene region and type I diabetes: application of flourescence-based technology to linkage disequilibrium mapping. Hum Mol Genet 1995; 4: 197–202.

    Article  CAS  PubMed  Google Scholar 

  61. Reed PW, Cucca F, Jenkins SC et al. Evidence for a type I diabetes susceptibility locus (IDDM10) on human chromosome 10p11–q11. Hum Mol Genet 1997; 6: 1011–1016.

    Article  CAS  PubMed  Google Scholar 

  62. Falconer M, Introduction to Quantitative Genetics, 4th edn. Longman: New York, 1996.

    Google Scholar 

  63. Neale MC, Cardon L . Methodologies for Genetic Studies of Twins and Families. Kluwer Academic Publishers: Dordrecht; 1992.

    Book  Google Scholar 

  64. Hall MA, Ahmadi KR, Norman PJ et al. Genetic influence on peripheral blood T lymphocyte levels. Genes Immun 2000; 1: 423–427.

    Article  CAS  PubMed  Google Scholar 

  65. Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  PubMed  Google Scholar 

  66. Amos CI . Robust variance-components approach for assesing genetic linkage in pedigrees. Am J Hum Genet 1994; 54: 535–543.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Fulker DW, Cherny SS, Sham PC, Hewitt JK . Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 1999; 64: 259–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pratt SC, Daly MJ, Kruglyak L . Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components. Am J Hum Genet 2000; 66: 1153–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hedrick PW . Gametic disequilibrium measures: proceed with caution. Genetics 1987; 117: 331–341.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lewontin RC . The interaction of selection and linkage. I. General considerations; heterotic models.Genetics 1964; 49: 49–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Xie X, Ott J . Testing linkage disequilibrium between a disease gene and a marker loci. Am J Hum Genet 1993; 53: 1107.

    Google Scholar 

  72. Zhao JH, Curtis D, Sham PC . Model-free analysis and permutation tests for allelic associations. Hum Heredity 2000; 50: 133–139.

    Article  CAS  PubMed  Google Scholar 

  73. Sobel E, Lange K . Descent graphs in pedigree analysis: application to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 1996; 58: 1323–1337.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Abecasis GR, Cookson WO . GOLD—graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the twins for participating and the clinical nurses and administration team for their work. KRA is supported by a Chronic Diseases Research Foundation Fellowship.

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Author notes

  1. K R Ahmadi

    Present address: Department of Biology, Galton Laboratories, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK

  2. 7 In September 2001 Gemini Genomics merged with Sequenom, 3595 John Hopkins Court, San Diego, CA, USA

Authors and Affiliations

  1. Twin Research & Genetic Epidemiology Unit, St Thomas' Hospital, Lambeth Palace Road, London, UK

    K R Ahmadi & T D Spector

  2. Department of Rheumatology, Molecular Immunogenetics Unit, GKT School of Medicine, King's College London, UK

    K R Ahmadi & J S Lanchbury

  3. Gemini Genomics plc7, UK

    P Reed, M Chiano, D Thompson, M Galley, A Line & E Lank

  4. Department of Chemical Pathology, Queen Mary's University Hospital, Roehampton Lane, London, UK

    H J Wong

  5. Department of Public Health Sciences, St George's Hospital Medical School, London, UK

    D Strachan

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  1. K R Ahmadi
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Ahmadi, K., Lanchbury, J., Reed, P. et al. Novel association suggests multiple independent QTLs within chromosome 5q21–33 region control variation in total humans IgE levels. Genes Immun 4, 289–297 (2003). https://doi.org/10.1038/sj.gene.6363968

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