Asthma and asthma-related traits are complex diseases with strong genetic and environmental components.
Association and genome-wide linkage studies have identified numerous candidate genes that are associated with asthma-related traits and are involved in innate immunity, T helper 2 cell differentiation and effector functions, epithelial cell biology and lung function.
The phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context.
Despite the achievements of asthma genetics, the identification of all the genes involved in disease, the replication of genotype–phenotype associations across populations, and the interactions of genes with environmental and developmental factors, and with one another, still represent formidable challenges.
The development of novel, powerful tools for gene discovery, such as genome-wide association studies, and a closer integration with biology, should help asthma geneticists to overcome these challenges.
Asthma and asthma-related traits are complex diseases with strong genetic and environmental components. Rapid progress in asthma genetics has led to the identification of several candidate genes that are associated with asthma-related traits. Typically the phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context. Despite the achievements made in asthma genetics formidable challenges remain. The development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology, should help to overcome these challenges.
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Los, H., Postmus, P. E. & Boomsma, D. I. Asthma genetics and intermediate phenotypes: a review from twin studies. Twin Res. 4, 81–93 (2001).
Cookson, W. O., Sharp, P. A., Faux, J. A. & Hopkin, J. M. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 333, 1292–1295 (1989).
Daniels, S. E. et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 383, 247–250 (1996).
Ober, C. & Hoffjan, S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun. 7, 95–100 (2006). An excellent review of 10 years of genetics of asthma and asthma-related traits.
Kurz, T. et al. Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci. J. Allergy Clin. Immunol. 118, 396–402 (2006).
Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).
Carlson, C. S., Eberle, M. A., Kruglyak, L. & Nickerson, D. A. Mapping complex disease loci in whole-genome association studies. Nature 429, 446–452 (2004). A balanced discussion of the toolkit of asthma genetics and the strengths and weaknesses of each major approach.
Cookson, W. The immunogenetics of asthma and eczema: a new focus on the epithelium. Nature Rev. Immunol. 4, 978–988 (2004).
Wills-Karp, M. & Ewart, S. L. Time to draw breath: asthma-susceptibility genes are identified. Nature Rev. Genet. 5, 376–387 (2004).
Bosse, Y. & Hudson, T. J. Toward a comprehensive set of asthma susceptibility genes. Annu. Rev. Med. 58, 171–184 (2007).
Guerra, S. & Martinez, F. D. Asthma genetics: from linear to multifactorial approaches. Annu. Rev. Med. 59, 199–213 (2008). A thoughtful discussion of phenotypic heterogeneity and gene–environment interactions in asthma.
Neale, B. M. & Sham, P. C. The future of association studies: gene-based analysis and replication. Am. J. Hum. Genet. 75, 353–362 (2004).
Baldini, M. et al. A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum IgE. Am. J. Respir. Cell. Mol. Biol. 20, 976–983 (1999).
Eder, W. et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J. Allergy Clin. Immunol. 113, 482–488 (2004). Together with references104–107, this paper provides strong evidence for gene–environment interactions in human populations.
Werner, M. et al. TLR4 gene variants modify endotoxin effects on asthma. J. Allergy Clin. Immunol. 112, 323–330 (2003).
Fageras Bottcher, M. et al. A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J. Allergy Clin. Immunol. 114, 561–567 (2004).
Tantisira, K. et al. Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun. 5, 343–346 (2004).
Lazarus, R. et al. Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol. Rev. 190, 9–25 (2002).
Hysi, P. et al. NOD1 variation, immunoglobulin E and asthma. Hum. Mol. Genet. 14, 935–941 (2005).
Kabesch, M. et al. Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J. Allergy Clin. Immunol. 111, 813–817 (2003).
Rosenstiel, P., Till, A. & Schreiber, S. NOD-like receptors and human diseases. Microbes Infect. 9, 648–657 (2007).
Hong, J. et al. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J. Gastroenterol. Hepatol. 22, 1760–1766 (2007).
Arroyo-Espliguero, R., Avanzas, P., Jeffery, S. & Kaski, J. C. CD14 and toll-like receptor 4: a link between infection and acute coronary events? Heart 90, 983–988 (2004).
Hobbs, K., Negri, J., Klinnert, M., Rosenwasser, L. J. & Borish, L. Interleukin-10 and transforming growth factor-β promoter polymorphisms in allergies and asthma. Am. J. Respir. Crit. Care Med. 158, 1958–1962 (1998).
Silverman, E. S. et al. Transforming growth factor-β1 promoter polymorphism C-509T is associated with asthma. Am. J. Respir. Crit. Care Med. 169, 214–219 (2004).
Litonjua, A. A. et al. Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma. Respir. Res. 6, 52 (2005).
Shiina, T., Inoko, H. & Kulski, J. K. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 64, 631–649 (2004).
Jinnai, N. et al. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum. Mol. Genet. 13, 3203–3217 (2004).
Traidl-Hoffmann, C. et al. Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization. J. Exp. Med. 201, 627–636 (2005).
Hwang, E. S., Szabo, S. J., Schwartzberg, P. L. & Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433 (2005).
Pykalainen, M. et al. Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes. J. Allergy Clin. Immunol. 115, 80–87 (2005).
Tantisira, K. G. et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc. Natl. Acad. Sci. USA 101, 18099–18104 (2004).
Kabesch, M. et al. A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood. J. Allergy Clin. Immunol. 112, 893–898 (2003).
Basehore, M. J. et al. A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects. J. Allergy Clin. Immunol. 114, 80–87 (2004).
Loza, M. J. & Chang, B. L. Association between Q551R IL4R genetic variants and atopic asthma risk demonstrated by meta-analysis. J. Allergy Clin. Immunol. 120, 578–585 (2007).
Schedel, M. et al. A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels. J. Allergy Clin. Immunol. 114, 1100–1105 (2004).
Morahan, G. et al. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 360, 455–459 (2002).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Ghaffar, O. et al. IL-13 mRNA and immunoreactivity in allergen-induced rhinitis: comparison with IL-4 expression and modulation by topical glucocorticoid therapy. Am. J. Respir. Cell. Mol. Biol. 17, 17–24 (1997).
Lordan, J. L. et al. Cooperative effects of TH2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J. Immunol. 169, 407–414 (2002).
Dealtry, G. B., Clark, D. E., Sharkey, A., Charnock-Jones, D. S. & Smith, S. K. Expression and localization of the TH2-type cytokine interleukin-13 and its receptor in the placenta during human pregnancy. Am. J. Reprod. Immunol. 40, 283–290 (1998).
Ribeiro-do-Couto, L. M. et al. High IL-13 production by human neonatal T cells: neonate immune system regulator? Eur. J. Immunol. 31, 3394–3402 (2001).
Wenzel, S., Wilbraham, D., Fuller, R., Getz, E. B. & Longphre, M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370, 1422–1431 (2007).
Vladich, F. D. et al. IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J. Clin. Invest. 115, 747–754 (2005). This paper demonstrates how functional studies can elucidate the contribution of genetic variants to disease susceptibility.
Graves, P. E. et al. 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, 506–513 (2000).
Liu, X. et al. 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, 167–170 (2000).
Wang, M. et al. A common IL-13 Arg130Gln single nucleotide polymorphism among Chinese atopy patients with allergic rhinitis. Hum. Genet. 113, 387–390 (2003).
Heinzmann, A. et al. Association study of the IL13 variant Arg110Gln in atopic diseases and juvenile idiopathic arthritis. J. Allergy Clin. Immunol. 112, 735–739 (2003).
Heinzmann, A. et al. Genetic variants of IL-13 signalling and human asthma and atopy. Hum. Mol. Genet. 9, 549–559 (2000).
He, J. Q. et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun. 4, 385–389 (2003).
Tsunemi, Y. et al. Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients. J. Dermatol. Sci. 30, 100–107 (2002).
DeMeo, D. et al. Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program. Genet. Epidemiol. 23, 335–348 (2002).
van der Pouw Kraan, T. C. et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun. 1, 61–65 (1999).
Howard, T. D. et al. 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, 377–384 (2001).
Hummelshoj, T. et al. Association between an interleukin-13 promoter polymorphism and atopy. Eur. J. Immunogenet. 30, 355–359 (2003).
Liu, X. et al. 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, 489–495 (2004).
Cameron, L. et al. TH2-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation. J. Immunol. 177, 8633–8642 (2006). This paper provides strong evidence for the existence of gene–environment interactions in the nucleus.
Shirakawa, T. et al. Association between atopy and variants of the β subunit of the high-affinity immunoglobulin E receptor. Nature Genet. 7, 125–129 (1994).
Donnadieu, E. et al. Competing functions encoded in the allergy-associated FcɛRIβ gene. Immunity 18, 665–674 (2003).
Kabesch, M. et al. Polymorphisms in eosinophil pathway genes, asthma and atopy. Allergy 62, 423–428 (2007).
Namkung, J. H. et al. IL-5 and IL-5 receptor α polymorphisms are associated with atopic dermatitis in Koreans. Allergy 62, 934–942 (2007).
Johansson, S., Wennergren, G., Aberg, N. & Rudin, A. Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells. J. Allergy Clin. Immunol. 120, 308–314 (2007).
Nickel, R. G. et al. Atopic dermatitis is associated with a functional mutation in the promoter of the C-C chemokine RANTES. J. Immunol. 164, 1612–1616 (2000).
Levy, H. et al. Association of defensin β-1 gene polymorphisms with asthma. J. Allergy Clin. Immunol. 115, 252–258 (2005).
Sengler, C. et al. Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J. Allergy Clin. Immunol. 111, 515–519 (2003).
Nakamura, H. et al. Variant eotaxin: its effects on the asthma phenotype. J. Allergy Clin. Immunol. 108, 946–953 (2001).
Chavanas, S. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nature Genet. 25, 141–142 (2000).
Walley, A. J. et al. Gene polymorphism in Netherton and common atopic disease. Nature Genet. 29, 175–178 (2001).
Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genet. 38, 441–446 (2006).
Marenholz, I. et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immunol. 118, 866–871 (2006).
Palmer, C. N. et al. Filaggrin null mutations are associated with increased asthma severity in children and young adults. J. Allergy Clin. Immunol. 120, 64–68 (2007).
Morar, N., Cookson, W. O., Harper, J. I. & Moffatt, M. F. Filaggrin mutations in children with severe atopic dermatitis. J. Invest. Dermatol. 127, 1667–1672 (2007).
Ying, S., Meng, Q., Corrigan, C. J. & Lee, T. H. Lack of filaggrin expression in the human bronchial mucosa. J. Allergy Clin. Immunol. 118, 1386–1388 (2006).
Hudson, T. J. Skin barrier function and allergic risk. Nature Genet. 38, 399–400 (2006).
Baurecht, H. et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J. Allergy Clin. Immunol. 120, 1406–1412 (2007).
Smith, F. J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genet. 38, 337–342 (2006).
Drysdale, C. M. et al. Complex promoter and coding region β 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc. Natl. Acad. Sci. USA 97, 10483–10488 (2000).
Moffatt, M. F. & Cookson, W. O. Tumour necrosis factor haplotypes and asthma. Hum. Mol. Genet. 6, 551–554 (1997).
Sayers, I. et al. Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma. Thorax 58, 417–424 (2003).
Fryer, A. A. et al. Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Am. J. Respir. Crit. Care Med. 161, 1437–1442 (2000).
Kabesch, M. et al. Glutathione S transferase deficiency and passive smoking increase childhood asthma. Thorax 59, 569–573 (2004).
Shin, H. D. et al. Association of thromboxane A2 receptor (TBXA2R) with atopy and asthma. J. Allergy Clin. Immunol. 112, 454–457 (2003).
Drazen, J. M. et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 22, 168–170 (1999).
Matsuda, A. et al. Coding SNP in tenascin-C Fn-III-D domain associates with adult asthma. Hum. Mol. Genet. 14, 2779–2786 (2005).
Gao, P. S. et al. Variants of NOS1, NOS2, and NOS3 genes in asthmatics. Biochem. Biophys. Res. Commun. 267, 761–763 (2000).
Hall, I. P. & Sayers, I. Pharmacogenetics and asthma: false hope or new dawn? Eur. Respir. J. 29, 1239–1245 (2007).
Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002). This paper reported the identification of ADAM33 , the first asthma susceptibility gene discovered by positional cloning.
Holgate, S. T. et al. Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur. Respir. J. 29, 793–803 (2007).
Zhang, Y. et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nature Genet. 34, 181–186 (2003).
Mellor, J. It takes a PHD to read the histone code. Cell 126, 22–24 (2006).
Allen, M. et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nature Genet. 35, 258–263 (2003).
Laitinen, T. et al. Characterization of a common susceptibility locus for asthma-related traits. Science 304, 300–304 (2004).
Nicolae, D. et al. Fine mapping and positional candidate studies identify HLA-G. as an asthma susceptibility gene on chromosome 6p21. Am. J. Hum. Genet. 76, 349–357 (2005).
Tan, Z. et al. Allele-specific targeting of microRNAs to HLA-G. and risk of asthma. Am. J. Hum. Genet. 81, 829–834 (2007).
Noguchi, E. et al. Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am. J. Respir. Crit. Care Med. 172, 183–188 (2005).
Balaci, L. et al. IRAK-M is involved in the pathogenesis of early-onset persistent asthma. Am. J. Hum. Genet. 80, 1103–1114 (2007).
Soderhall, C. et al. Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol. 5, e242 (2007).
Editorial. Framework for a fully powered risk engine. Nature Genet. 37, 1153 (2005).
Hall, I. P. & Blakey, J. D. Genetic association studies in Thorax. Thorax 60, 357–359 (2005).
Chanock, S. J. et al. Replicating genotype-phenotype associations. Nature 447, 655–660 (2007). This paper provides a thoughtful and in-depth discussion of how the results of association studies and their replication, or lack thereof, should be interpreted.
Hersh, C. P. et al. Comprehensive testing of positionally cloned asthma genes in two populations. Am. J. Respir. Crit. Care Med. 176, 849–857 (2007).
Maier, L. M. et al. Association of IL13 with total IgE: Evidence against an inverse association of atopy and diabetes. J. Allergy Clin. Immunol. 117, 1306–1313 (2006).
von Mutius, E. Influences in allergy: epidemiology and the environment. J. Allergy Clin. Immunol. 113, 373–379 (2004).
Valdar, W. et al. Genetic and environmental effects on complex traits in mice. Genetics 174, 959–984 (2006).
Martinez, F. D. Gene–environment interactions in asthma and allergies: a new paradigm to understand disease causation. Immunol. Allergy Clin. North Am. 25, 709–721 (2005).
Finberg, R. W. & Kurt-Jones, E. A. CD14: chaperone or matchmaker? Immunity 24, 127–129 (2006).
Lee, H. K., Dunzendorfer, S., Soldau, K. & Tobias, P. S. Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 24, 153–163 (2006).
LeVan, T. D. et al. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J. Immunol. 167, 5838–5844 (2001).
Jones, C. A. et al. Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both. J. Allergy Clin. Immunol. 109, 858–866 (2002).
Leynaert, B. et al. Association between farm exposure and atopy, according to the CD14 C-159T polymorphism. J. Allergy Clin. Immunol. 118, 658–665 (2006).
Ober, C., Tsalenko, A., Parry, R. & Cox, N. J. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am. J. Hum. Genet. 67, 1154–1162 (2000).
Woo, J., Assa'ad, A., Heizer, A., Bernstein, J. & Hershey, G. The-59 C→T polymorphism of CD14 is associated with nonatopic asthma and food allergy. J. Allergy Clin. Immunol. 112, 438–444 (2003).
Sengler, C. et al. Evaluation of the CD14 C-159T polymorphism in the German MAS cohort. Clin. Exp. Allergy 33, 166–169 (2003).
Kabesch, M. et al. A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases. Allergy 59, 520–525 (2004).
Kedda, M. A. et al. The CD14 C-159T polymorphism is not associated with asthma or asthma severity in an Australian adult population. Thorax 60, 211–214 (2005).
Vercelli, D. Genetics, epigenetics and the environment: switching, buffering, releasing. J. Allergy Clin. Immunol. 113, 381–386 (2004).
Eder, W. et al. Opposite effects of CD14/-260 on serum IgE levels in children raised in different environments. J. Allergy Clin. Immunol. 116, 601–607 (2005).
Zambelli-Weiner, A. et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J. Allergy Clin. Immunol. 115, 1203–1209 (2005).
Gern, J. E. et al. Effects of dog ownership and genotype on immune development and atopy in infancy. J. Allergy Clin. Immunol. 113, 307–314 (2004).
Simpson, A. et al. Endotoxin exposure, CD14 and allergic disease: an interaction between genes and the environment. Am. J. Respir. Crit. Care Med. 174, 386–392 (2006).
Meyers, D. A. et al. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J. Allergy Clin. Immunol. 115, 1169–1175 (2005).
Weiss, L. A., Pan, L., Abney, M. & Ober, C. The sex-specific genetic architecture of quantitative traits in humans. Nature Genet. 38, 218–222 (2006).
Vercelli, D. Learning from discrepancies: CD14 polymorphisms, atopy and the endotoxin switch. Clin. Exp. Allergy 33, 153–155 (2003).
Kabesch, M. et al. IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. J. Allergy Clin. Immunol. 117, 269–274 (2006). This work highlighted gene–gene interactions along the T H 2-cell-associated signalling pathway that might be important for allergy and asthma risk.
Howard, T. D. et al. Gene–gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am. J. Hum. Genet. 70, 230–236 (2002).
Chan, I. H. et al. Gene–gene interactions for asthma and plasma total IgE concentration in Chinese children. J. Allergy Clin. Immunol. 117, 127–133 (2006).
Moffatt, M. F. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007). This paper reported the results of the first GWA study for an asthma phenotype.
Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005).
The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). This paper provides an eloquent demonstration of the power of GWA studies and an in-depth discussion of issues related to study design, sample size and phenotyping.
Vercelli, D. & Martinez, F. D. The Faustian bargain of genetic association studies: bigger might not be better, or at least it might not be good enough. J. Allergy Clin. Immunol. 117, 1303–1305 (2006).
Christensen, K. & Murray, J. C. What genome-wide association studies can do for medicine. N. Engl. J. Med. 356, 1094–1097 (2007).
Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
Williams, S. M. et al. Problems with genome-wide association studies. Science 316, 1840–1842 (2007).
Hjelmqvist, L. et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol. 3, research0027.1–0027.16 (2002).
Farrall, M. Quantitative genetic variation: a post-modern view. Hum. Mol. Genet. 13 (Spec. No. 1), R1–R7 (2004).
Martinez, F. D. Toward asthma prevention — does all that really matters happen before we learn to read? N. Engl. J. Med. 349, 1473–1475 (2003).
Ege, M. J. et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 117, 817–823 (2006).
O'Donnell, A. R. et al. Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years. Am. J. Respir. Crit. Care Med. 169, 615–622 (2004).
Cropley, J., Suter, C., Beckman, K. & Martin, D. Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation. Proc. Natl. Acad. Sci. USA 103, 17308–17312 (2006).
Rutherford, S. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).
Queitsch, C., Sangster, T. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002).
Kaati, G., Bygren, L. O., Pembrey, M. & Sjostrom, M. Transgenerational response to nutrition, early life circumstances and longevity. Eur. J. Hum. Genet. 15, 784–790 (2007).
Webster, R. B., Rodriguez, Y., Klimecki, W. T. & Vercelli, D. The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. J. Biol. Chem. 282, 700–709 (2007).
Santangelo, S., Cousins, D. J., Winkelmann, N. E. & Staynov, D. Z. DNA methylation changes at human TH2 cytokine genes coincide with DNase I hypersensitive site formation during CD4+ T cell differentiation. J. Immunol. 169, 1893–1903 (2002).
Barnes, P. J., Adcock, I. M. & Ito, K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur. Respir. J. 25, 552–563 (2005).
Hoffjan, S. et al. Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy. J. Allergy Clin. Immunol. 113, 511–518 (2004).
Holloway, J. W. & Koppelman, G. H. Identifying novel genes contributing to asthma pathogenesis. Curr. Opin. Allergy Clin. Immunol. 7, 69–74 (2007).
Leung, T. F. et al. A polymorphism in the coding region of interleukin-13 gene is associated with atopy but not asthma in Chinese children. Clin. Exp. Allergy 31, 1515–1521 (2001).
Leung, T. F. et al. Association between candidate genes and lung function growth in Chinese asthmatic children. Clin. Exp. Allergy 37, 1480–1486 (2007).
Chen, W., Ericksen, M. B., Levin, L. S. & Khurana Hershey, G. K. Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants. J. Allergy Clin. Immunol. 114, 553–560 (2004).
The propensity of an individual to develop allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever. It is defined operationally by elevations in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.
- Population structure
Any deviation from the ideal state of a single population in which every individual has the same chance of mating with every other.
- Single nucleotide polymorphisms
(SNPs). Variations in DNA sequence in which one of the four nucleotides is substituted for another (for example, C for A). SNPs are the most frequent type of polymorphism in the genome.
- Tag SNP
A single nucleotide polymorphism (SNP) that is correlated with a neighbouring variant, which serves as a proxy for that (not genotyped) variant.
- TH2 cells
CD4+ T helper (TH) cells differentiated along a pathway that leads to coordinated expression of IL-4, IL-13 and IL-5. TH2 cells and their cytokine products are central mediators of allergic inflammation.
- Positional cloning
The process of systematically identifying mutations or susceptibility alleles by studying genetic markers in families or high-risk individuals.
- Pattern recognition receptors
Proteins expressed by innate immune cells that detect molecules associated with microbial pathogens or cellular stress.
- Quantitative-trait locus
A polymorphic locus that contains alleles that differentially affect the expression of a continuously distributed phenotypic trait (for example, total serum IgE levels).
Polymorphic DNA loci that consist of repeating units of 1–4 bp in length.
- Linkage disequilibrium map
Map of non-random associations between alleles at two or more loci.
A combination of alleles at different markers located on the same chromosome in a specific genomic region.
Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.
The study of heritable changes in gene function that occur without a change in the DNA sequence.
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Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8, 169–182 (2008). https://doi.org/10.1038/nri2257
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