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Asthma genetics 2006: the long and winding road to gene discovery

Abstract

Asthma and atopy are complex phenotypes that are influenced by both genetic and environmental factors. A review of nearly 500 papers on disease association studies identified 25 genes that have been associated with an asthma or atopy phenotype in six or more populations. An additional 54 genes have been associated in 2–5 populations. Here, we discuss the methods that have been used to identify susceptibility genes for common diseases and overview the status of asthma genetic research. Finally, current challenges and future directions are discussed.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Watson JD, Cook-Deegan RM . The human genome project and international health. JAMA 1990; 263: 3322–3324.

    Article  CAS  PubMed  Google Scholar 

  3. Friedmann T . The human genome project – some implications of extensive ‘reverse genetic’ medicine. Am J Hum Genet 1990; 46: 407–414.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Collins FS . The Genome Project and human health. FASEB J 1991; 5: 77.

    Article  CAS  PubMed  Google Scholar 

  5. Collins FS . Positional cloning moves from perditional to traditional. Nature Genet 1995; 9: 347–350.

    Article  CAS  PubMed  Google Scholar 

  6. Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003; 35: 258–263.

    Article  CAS  PubMed  Google Scholar 

  7. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P et al. Characterization of a common susceptibility locus for asthma-related traits. Science 2004; 304: 300–304.

    Article  CAS  PubMed  Google Scholar 

  8. Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005; 76: 349–357.

    Article  CAS  PubMed  Google Scholar 

  9. Noguchi E, Yokouchi Y, Zhang J, Shibuya K, Shibuya A, Bannai M et al. Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am J Respir Crit Care Med 2005; 172: 183–188.

    Article  PubMed  Google Scholar 

  10. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–430.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003; 34: 181–186.

    Article  CAS  PubMed  Google Scholar 

  12. Kleeberger SR, Peden D . Gene-environment interactions in asthma and other respiratory diseases. Annu Rev Med 2005; 56: 383–400.

    Article  CAS  PubMed  Google Scholar 

  13. Mapp CE . Genetics and the occupational environment. Curr Opin Allergy Clin Immunol 2005; 5: 113–118.

    Article  CAS  PubMed  Google Scholar 

  14. Ober C . Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol 2005; 116: 274–278.

    Article  CAS  PubMed  Google Scholar 

  15. Ober C, Thompson EE . Rethinking genetic models of asthma: the role of environmental modifiers. Curr Opin Immunol 2005; 17: 670–680.

    Article  CAS  PubMed  Google Scholar 

  16. Singh J, Schwartz DA . Endotoxin and the lung: Insight into the host-environment interaction. J Allergy Clin Immunol 2005; 115: 330–333.

    Article  CAS  PubMed  Google Scholar 

  17. Cookson W, Moffatt M . Making sense of asthma genes. N Engl J Med 2004; 351: 1794–1796.

    Article  CAS  PubMed  Google Scholar 

  18. Wills-Karp M, Ewart SL . Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 2004; 5: 376–387.

    Article  CAS  PubMed  Google Scholar 

  19. Halapi E, Hakonarson H . Recent development in genomic and proteomic research for asthma. Curr Opin Pulm Med 2004; 10: 22–30.

    Article  CAS  PubMed  Google Scholar 

  20. Kere J, Laitinen T . Positionally cloned susceptibility genes in allergy and asthma. Curr Opin Immunol 2004; 16: 689–694.

    Article  CAS  PubMed  Google Scholar 

  21. Weiss ST, Raby BA . Asthma genetics 2003. Hum Mol Genet 2004; 13 (Spec no. 1): R83–R89.

    Article  CAS  PubMed  Google Scholar 

  22. Holgate ST, Davies DE, Powell RM, Holloway JW . ADAM33: a newly identified protease involved in airway remodelling. Pulm Pharmacol Ther 2005; 19: 3–11.

    Article  PubMed  Google Scholar 

  23. Ober C . HLA-G: an asthma gene on chromosome 6p. Immunol Allergy Clin North Am 2005; 25: 669–679.

    Article  PubMed  Google Scholar 

  24. Vendelin J, Pulkkinen V, Rehn M, Pirskanen A, Raisanen-Sokolowski A, Laitinen A et al. Characterization of GPRA, a novel G protein-coupled receptor related to asthma. Am J Respir Cell Mol Biol 2005; 33: 262–267.

    Article  CAS  PubMed  Google Scholar 

  25. Hoffjan S, Ober C . Present status on the genetic studies of asthma. Curr Opin Immunol 2002; 14: 709–717.

    Article  CAS  PubMed  Google Scholar 

  26. Baldini M, Vercelli D, Martinez FD . CD14: an example of gene by environment interaction in allergic disease. Allergy 2002; 57: 188–192.

    Article  CAS  PubMed  Google Scholar 

  27. McIntire JJ, Umetsu SE, Macaubas C, Hoyte EG, Cinnioglu C, Cavalli-Sforza LL et al. Immunology: hepatitis A virus link to atopic disease. Nature 2003; 425: 576.

    Article  CAS  PubMed  Google Scholar 

  28. Zambelli-Weiner A, Ehrlich E, Stockton ML, Grant AV, Zhang S, Levett PN et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 2005; 115: 1203–1209.

    Article  CAS  PubMed  Google Scholar 

  29. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R . Association between genetic polymorphisms of the b2-adrenergic receptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997; 100: 3184–3188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Raby BA, Silverman EK, Lazarus R, Lange C, Kwiatkowski DJ, Weiss ST . Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes. Hum Mol Genet 2003; 12: 1973–1979.

    Article  CAS  PubMed  Google Scholar 

  31. Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6: 95–108.

    Article  CAS  PubMed  Google Scholar 

  32. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  33. Spielman RS, Ewens WJ . The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59: 983–989.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Devlin B, Roeder K . Genomic control for association studies. Biometrics 1999; 55: 997–1004.

    Article  CAS  PubMed  Google Scholar 

  35. Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hu N, Wang C, Hu Y, Yang HH, Giffen C, Tang ZZ et al. Genome-wide association study in esophageal cancer using GeneChip mapping 10 K array. Cancer Res 2005; 65: 2542–2546.

    Article  CAS  PubMed  Google Scholar 

  37. Ozaki K, Tanaka T . Genome-wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cell Mol Life Sci 2005; 62: 1804–1813.

    Article  CAS  PubMed  Google Scholar 

  38. Yamamoto K, Yamada R . Genome-wide single nucleotide polymorphism analyses of rheumatoid arthritis. J Autoimmun 2005; 255: 12–15.

    Article  Google Scholar 

  39. Hoffjan S, Nicolae D, Ober C . Association studies for asthma and atopic diseases: a comprehensive review of the literature. Respir Res 2003; 4: 14–28.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Neale BM, Sham PC . The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Consortium TIH . A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

    Article  Google Scholar 

  42. van der Pouw Kraan TCTM, van Veen A, Boeije LCM, van Yurl SAP, de Groot ER, Stapel SO et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1999; 1: 61–65.

    Article  CAS  PubMed  Google Scholar 

  43. Vladich FD, Brazille SM, Stern D, Peck ML, Ghittoni R, Vercelli D . IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J Clin Invest 2005; 115: 747–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Baldini M, Lohman IC, Halonen M, Erickson RP, Hold PG, Martinez FD . A polymorphism in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999; 20: 976–983.

    Article  CAS  PubMed  Google Scholar 

  45. Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M et al. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 1995; 25: 74–78.

    Article  PubMed  Google Scholar 

  46. Blakey J, Halapi E, Bjornsdottir US, Wheatley A, Kristinsson S, Upmanyu R et al. Contribution of ADAM33 polymorphisms to the population risk of asthma. Thorax 2005; 60: 274–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG . Replication validity of genetic association studies. Nat Genet 2001; 29: 306–309.

    Article  CAS  PubMed  Google Scholar 

  48. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  PubMed  Google Scholar 

  49. Traherne JA, Hill MR, Hysi P, D'Amato M, Broxholme J, Mott R et al. LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta. Hum Mol Genet 2003; 12: 2577–2585.

    Article  CAS  PubMed  Google Scholar 

  50. Weiss LA, Pan L, Abney M, Ober C . The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 2006, in press.

  51. Hakonarson H, Bjornsdottir US, Halapi E, Bradfield J, Zink F, Mouy M et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci USA 2005; 102: 14789–14794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zimmermann N, Mishra A, King NE, Fulkerson PC, Doepker MP, Nikolaidis NM et al. Transcript signatures in experimental asthma: identification of STAT6-dependent and -independent pathways. J Immunol 2004; 172: 1815–1824.

    Article  CAS  PubMed  Google Scholar 

  53. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS et al. Genetic analysis of genome-wide variation in human gene expression. Nature 2004; 430: 743–747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krauthammer M, Kaufmann CA, Gilliam TC, Rzhetsky A . Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease. Proc Natl Acad Sci USA 2004; 101: 15148–15153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 2005; 437: 1173–1178.

    Article  CAS  PubMed  Google Scholar 

  56. Shilling RA, Pinto JM, Decker DC, Schneider DH, Bandukawala HS, Schneider JR et al. Cutting edge: polymorphisms in the ICOS promoter region are associated with allergic sensitization and th2 cytokine production. J Immunol 2005; 175: 2061–2065.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Nancy Cox for helpful discussions and Ms Kathrin Zeller for assistance with preparing this manuscript. This work was supported in part by NIH Grants HL56399, HL66533, HL70831, and HL72414 to CO and by the ‘Forschungsförderung der Ruhr-Universität Bochum Medizinische Fakultät’ (FoRUM) Grants #F377-03 and #F480-05 to SH.

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Correspondence to C Ober.

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Supplementary Information accompanies the paper on Genes and Immunity's website (http://www.nature.com/gene)

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Ober, C., Hoffjan, S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 7, 95–100 (2006). https://doi.org/10.1038/sj.gene.6364284

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