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Functional Genomics of Allergic Diseases

  • Donata Vercelli
Part of the Allergy Frontiers book series (ALLERGY, volume 1)

Allergic inflammation and its most common phenotypes (asthma, allergy and atopic dermatitis) are one of the most eloquent examples of human complex diseases, disorders caused by a constellation of genetic hits that are individually mild but lead to major phenotypic effects when they act on multiple steps along a mechanistic pathway. The literature is rich in association and linkage studies pointing to candidate genes that might act as critical determinants of allergy/asthma susceptibility. However, the abundance of single nucleotide polymorphisms (SNPs) in the human genome, and the complex patterns of linkage disequilibrium (LD) found at most genetic loci, prevent the tools of genetic epidemiology from deciphering the contribution of individual polymorphisms to increased disease risk. As a result, the mechanisms underlying the associations between patterns of genetic variation and disease phenotypes are in most cases unclear. Functional genomics studies provide a powerful tool to understand how genetic factors affect the pathogenesis of, and the susceptibility to, complex diseases such as allergic inflammation.

Functional genomics is still in its infancy. Indeed, as yet there is no universally accepted approach to defining the impact of genetic variants on gene expression and/or function. Interestingly, the more we experiment, the more we realize how subtle, even devious, the effects of genetic variants can be, and how lightly we must tread on the uncharted ground of functional genomics. Here we shall briefly review some of the results our group recently obtained studying the functional genomics of interleukin (IL)13, a major candidate gene for allergic inflammation [1, 2], and we shall discuss how our findings have contributed to advancing the field of functional genomics.

Keywords

Atopic Dermatitis Allergic Disease Functional Genomic Allergy Clin Immunol Allergic Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Wills-Karp M (2004) Interleukin-13 in asthma pathogenesis. Immunol Rev 202:175–190CrossRefGoogle Scholar
  2. 2.
    Cohn L, Elias JA, Chupp GL (2004) Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 22:789–815PubMedCrossRefGoogle Scholar
  3. 3.
    Graves PE, Kabesch M, Halonen M, et al (2000) A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 105:506–513PubMedCrossRefGoogle Scholar
  4. 4.
    Hoffjan S, Nicolae D, Ober C (2003) Association studies for asthma and atopic diseases: a comprehensive review of the literature. Respir Res 4:14PubMedCrossRefGoogle Scholar
  5. 5.
    Liu X, Nickel R, Beyer K, et al (2000) An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 106:167–170PubMedCrossRefGoogle Scholar
  6. 6.
    Wang M, Xing Z, Lu C, et al (2003) A common IL-13 Arg130Gln single nucleotIDe polymorphism among Chinese atopy patients with allergic rhinitis. Hum Genet 113:387–390PubMedCrossRefGoogle Scholar
  7. 7.
    Heinzmann A, Jerkic SP, Ganter K, et al (2003) Association study of the IL13 variant Arg110Gln in atopic diseases and juvenile IDiopathic arthritis. J Allergy Clin Immunol 112:735–739PubMedCrossRefGoogle Scholar
  8. 8.
    Hoffjan S, Ostrovnaja I, Nicolae D, et al (2004) Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy. J Allergy Clin Immunol 113:511–518PubMedCrossRefGoogle Scholar
  9. 9.
    Maier LM, Howson JMM, Walker N, et al (2006) Association of IL13 with total IgE: EvIDence against an inverse association of atopy and diabetes. J Allergy Clin Immunol 117:1306–1313PubMedCrossRefGoogle Scholar
  10. 10.
    Heinzmann A, Mao X, Akaiwa M, et al (2000) Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 9:549–559PubMedCrossRefGoogle Scholar
  11. 11.
    He JQ, Chan-Yeung M, Becker AB, et al (2003) Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 4:385–389PubMedCrossRefGoogle Scholar
  12. 12.
    Tsunemi Y, Saeki H, Nakamura K, et al (2002) Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients. J Dermatol Sci 30:100–107PubMedCrossRefGoogle Scholar
  13. 13.
    DeMeo D, Lange C, Silverman E, et al (2002) Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program. Genet EpIDemiol 23:335–348PubMedCrossRefGoogle Scholar
  14. 14.
    van der Pouw Kraan TCTM, van Veen A, Boeije LCM, et al (1999) An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1:61–65PubMedCrossRefGoogle Scholar
  15. 15.
    Howard TD, Whittaker PA, Zaiman AL, et al (2001) IDentification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol 25:377–384PubMedGoogle Scholar
  16. 16.
    Liu X, Beaty T, Deindl P, et al (2003) Associations between total serum IgE levels and the 6 potentially functional variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study. J Allergy Clin Immunol 112:382–388PubMedCrossRefGoogle Scholar
  17. 17.
    Hummelshoj T, Bodtger U, Datta P, et al (2003) Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 30:355–359PubMedCrossRefGoogle Scholar
  18. 18.
    Brown RH, Hamilton RG, Mintz M, et al (2005) Genetic predisposition to latex allergy: role of interleukin 13 and interleukin 18. Anesthesiology 102:496–502PubMedCrossRefGoogle Scholar
  19. 19.
    MoissIDis I, Chinoy B, Yanamandra K, et al (2005) Association of IL-13, RANTES, and leukotriene C4 synthase gene promoter polymorphisms with asthma and/or atopy in African Americans. Genet Med 7:406–410PubMedCrossRefGoogle Scholar
  20. 20.
    Howard TD, Koppelman GH, Xu J, et al (2002) Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 70:230–236PubMedCrossRefGoogle Scholar
  21. 21.
    Liu X, Beaty TH, Deindl P, et al (2004) Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study. J Allergy Clin Immunol 113:489–495PubMedCrossRefGoogle Scholar
  22. 22.
    Kabesch M, Schedel M, Carr D, et al (2006) IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. J Allergy Clin Immunol 117:269–274PubMedCrossRefGoogle Scholar
  23. 23.
    Chan IH, Leung TF, Tang NL, et al (2006) Gene-gene interactions for asthma and plasma total IgE concentration in Chinese children. J Allergy Clin Immunol 117:127–133PubMedCrossRefGoogle Scholar
  24. 24.
    Arima K, Umeshita-Suyama R, Sakata Y, et al (2002) Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma. J Allergy Clin Immunol 109:980–987PubMedCrossRefGoogle Scholar
  25. 25.
    Chen W, Ericksen MB, Levin LS, et al (2004) Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants. J Allergy Clin Immunol 114:553–560PubMedCrossRefGoogle Scholar
  26. 26.
    Madhankumar AB, Mintz A, Debinski W (2002) Alanine-scanning mutagenesis of alpha-helix D segment of interleukin-13 reveals new functionally important resIDues of the cytokine. J Biol Chem 277:43194–43205PubMedCrossRefGoogle Scholar
  27. 27.
    Vladich FD, Brazille SM, Stern D, et al (2005) IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J Clin Invest 115:747–754PubMedGoogle Scholar
  28. 28.
    Minty A, Chalon P, Derocq JM, et al (1993) Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 362:248–250PubMedCrossRefGoogle Scholar
  29. 29.
    Carlson CS, Eberle MA, et al (2004) Mapping complex disease loci in whole-genome association studies. Nature 429:446–452PubMedCrossRefGoogle Scholar
  30. 30.
    Donaldson DD, Whitters MJ, Fitz LJ, et al (1998) The murine IL-13 receptor α2: Molecular cloning, characterization and comparison with murine IL-13 receptor α1. J Immunol 161:2317–2324PubMedGoogle Scholar
  31. 31.
    Wood N, Whitters MJ, Jacobson BA, et al (2003) Enhanced interleukin-13 responses in mice lacking IL-13 receptor α 2. J Exp Med 197:703–709PubMedCrossRefGoogle Scholar
  32. 32.
    Zheng T, Zhu Z, Liu W, et al (2003) Cytokine regulation of IL-13Rα2 and IL-13Rα1 in vivo and in vitro. J Allergy Clin Immunol 111:720–728PubMedCrossRefGoogle Scholar
  33. 33.
    LeVan TD, Bloom JW, Bailey TJ, et al (2001) A common single nucleotIDe polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 167:5838–5844PubMedGoogle Scholar
  34. 34.
    Schweiger A, Stern D, Lohman IC, et al (2001) Differences in proliferation of the hematopoi-etic cell line TF-1 and cytokine production by peripheral blood leukocytes induced by 2 naturally occurring forms of human IL-3. J Allergy Clin Immunol 107:505–510PubMedCrossRefGoogle Scholar
  35. 35.
    Knight JC, Keating BJ, Kwiatkowski DP (2004) Allele-specific repression of lymphotoxin-α by activated B cell factor-1. Nat Genet 36:394–399PubMedCrossRefGoogle Scholar
  36. 36.
    Cameron L, Webster RB, Strempel JM, et al (2006) Th2-selective enhancement of human IL13 transcription by IL13–1112C > T, a polymorphism associated with allergic inflammation. J Immunol 177:8633–8642PubMedGoogle Scholar
  37. 37.
    Boffelli D, McAuliffe J, Ovcharenko D, et al (2003) Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science 299:1391–1394PubMedCrossRefGoogle Scholar
  38. 38.
    Webster RB, Rodriguez Y, Klimecki WT, et al (2007) The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. J Biol Chem 282:700–709PubMedCrossRefGoogle Scholar
  39. 39.
    Agarwal S, Rao A (1998) Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9:765–775PubMedCrossRefGoogle Scholar
  40. 40.
    Ober C, Hoffjan S (2006) Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 7:95–100PubMedCrossRefGoogle Scholar
  41. 41.
    Georas SN, Cumberland JE, Burke TF, et al (1998) Stat6 inhibits human interleukin-4 promoter activity in T cells. Blood 92:4529–4538PubMedGoogle Scholar
  42. 42.
    Gordon S, Akopyan G, Garban H, et al (2006) Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25:1125–1142PubMedCrossRefGoogle Scholar
  43. 43.
    Oddy WH, Halonen M, Martinez FD, et al (2003) TGF-β in human milk is associated with wheeze in infancy. J Allergy Clin Immunol 112:723–728PubMedCrossRefGoogle Scholar
  44. 44.
    Lohmueller KE, Pearce CL, Pike M, et al (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182PubMedCrossRefGoogle Scholar
  45. 45.
    Editorial (2005) Framework for a fully powered risk engine. Nat Genet 37:1153CrossRefGoogle Scholar
  46. 46.
    Hall IP, Blakey JD (2005) Genetic association studies in Thorax. Thorax 60:357–359PubMedCrossRefGoogle Scholar
  47. 47.
    Tokuhiro S, Yamada R, Chang X, et al (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoID arthritis. Nat Genet 35:341–348PubMedCrossRefGoogle Scholar
  48. 48.
    Silverman ES, Palmer LJ, Subramaniam V, et al (2004) Transforming growth factor-β1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med 169:214–219PubMedCrossRefGoogle Scholar
  49. 49.
    Di Rienzo A, Hudson RR (2005) An evolutionary framework for common diseases: The ancestral susceptibility model. Trends Genet 21: 596–601PubMedCrossRefGoogle Scholar
  50. 50.
    Kouriba B, Chevillard C, Bream J, et al (2005) Analysis of the 5q31–q33 locus shows an association between IL13–1055C/T IL-13–591A/G polymorphisms and Schistosoma haema-tobiuminfections. J Immunol 174:6274–6281PubMedGoogle Scholar
  51. 51.
    Ohashi J, Naka I, Patarapotikul J, et al (2003) A single-nucleotIDe substitution from C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand. Genes Immun 4:528–531PubMedCrossRefGoogle Scholar
  52. 52.
    Zhou G, Zhai Y, Dong X, et al (2004) Haplotype structure and evIDence for positive selection at the human IL13 locus. Mol Biol Evol 21:29–35PubMedCrossRefGoogle Scholar
  53. 53.
    Chegini N, Roberts M, Ripps B (2003) Differential expression of interleukins (IL)-13 and IL-15 in ectopic and eutopic endometrium of women with endometriosis and normal fertile women. Am J Reprod Immunol 49:75–83PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Donata Vercelli
    • 1
  1. 1.Arizona Respiratory Center and Department of Cell Biology, College of Medicine, and The Bio5 InstituteUniversity of ArizonaTucson

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