Gen-Gen- und Gen-Umwelt-Interaktionsanalysen bei Kindern der Multizentrischen Allergie StudiePhilipp Deindl aus Mannheim 111.11.21.2.121.2.21.2.2.131.2.2.2567#2181.2.2.345274#1041.2.2.46239#1401.2.2.5315#1321.2.371.2.41.2.581.2.61.31.3.11.3.1.191.3.2101.3.3111.3.412445#3341.3.51.3.5.113286#2861.3.5.214379#23215568#343161.3.61.3.6.1306#241171.3.6.21.3.6.3181.3.6.41.3.6.5191.3.7201.3.7.11.3.7.21.4211.4.11.4.21.4.2.11.4.2.2221.4.2.31.4.2.3.123241.4.2.425548#4271.4.31.4.3.11.4.3.2261.4.3.3271.4.3.4281.4.4291.4.4.11.4.4.21.4.4.3301.4.4.42313323.13.1.133447#2903435423#367363.1.2373.1.3383.23.2.1393.2.2403.2.33.2.43.2.53.2.63.3413.3.13.3.23.3.3423.3.44344570#3013.3.545148#208567#833.3.6463.3.73.3.7.13.3.7.247482#24748567#67949503.3.851523.3.8.14534.14.1.1544.1.255566#68456567#68857584.1.34.1.3.1594.1.3.260474#3374.26162576#2164.363564655.15.1.16667685.2695.35.3.170715.3.2725.3.35.473745.55.6755.6.15.6.25.6.3765.6.45.6.577678Abkürzungen Literatur79 Danksagung94 Lebenslauf95 Eidesstattliche Erklärung96deInhaltsverzeichnisHilfe Literatur [1] Schramm, B.; Ehlken, B.; Smala, A.; Quednau, K.; Berger, K. and Nowak, D. (2003): Cost of illness of atopic asthma and seasonal allergic rhinitis in Germany: 1-yr retrospective study, Eur Respir J, (vol. 21), No. 1, pp.116-22.. [2] Illi, S.; von Mutius, E.; Lau, S.; Bergmann, R.; Niggemann, B.; Sommerfeld, C. and Wahn, U. (2001): Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study, Bmj, (vol. 322), No. 7283, pp.390-5.. [3] von Mutius, E.; Braun-Fahrlander, C.; Schierl, R.; Riedler, J.; Ehlermann, S.; Maisch, S.; Waser, M. and Nowak, D. (2000): Exposure to endotoxin or other bacterial components might protect against the development of atopy, Clin Exp Allergy, (vol. 30), No. 9, pp.1230-4.. [4] von Mutius, E.; Martinez, F. D.; Fritzsch, C.; Nicolai, T.; Roell, G. and Thiemann, H. H. (1994): Prevalence of asthma and atopy in two areas of West and East Germany, Am J Respir Crit Care Med, (vol. 149), No. 2 Pt 1, pp.358-64.. [5] Sandford, A.; Weir, T. and Pare, P. (1996): The genetics of asthma, Am J Respir Crit Care Med, (vol. 153), No. 6 Pt 1, pp.1749-65.. [6] Skadhauge, L. R.; Christensen, K.; Kyvik, K. O. and Sigsgaard, T. (1999): Genetic and environmental influence on asthma: a population-based study of 11,688 Danish twin pairs, Eur Respir J, (vol. 13), No. 1, pp.8-14.. [7] Sengler, C.; Lau, S.; Wahn, U. and Nickel, R. (2002): Interactions between genes and environmental factors in asthma and atopy: new developments, Respir Res, (vol. 3), No. 1, p.7.. [8] de Vries, J. E. (1998): The role of IL-13 and its receptor in allergy and inflammatory responses, J Allergy Clin Immunol, (vol. 102), No. 2, pp.165-9.. [9] Izuhara, K. and Shirakawa, T. (1999): Signal transduction via the interleukin-4 receptor and its correlation with atopy, Int J Mol Med, (vol. 3), No. 1, pp.3-10.. [10] Wills-Karp, M. (2001): IL-12/IL-13 axis in allergic asthma, J Allergy Clin Immunol, (vol. 107), No. 1, pp.9-18.. [11] Vercelli, D. (1993): Regulation of IgE synthesis, Allergy Proc, (vol. 14), No. 6, pp.413-6.. [12] Terada, N.; Hamano, N.; Hohki, G.; Ikeda, T.; Sai, M.; Yamashita, T. and Konno, A. (1998): The potential role of interleukin-13 in eosinophilic inflammation in nasal mucosa, Allergy, (vol. 53), No. 7, pp.690-7.. [13] Matsukura, S.; Stellato, C.; Georas, S. N.; Casolaro, V.; Plitt, J. R.; Miura, K.; Kurosawa, S.; Schindler, U. and Schleimer, R. P. (2001): Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism, Am J Respir Cell Mol Biol, (vol. 24), No. 6, pp.755-61.. [14] Wills-Karp, M. (2000): The gene encoding interleukin-13: a susceptibility locus for asthma and related traits, Respir Res, (vol. 1), No. 1, pp.19-23.. [15] Walley, A. J.; Wiltshire, S.; Ellis, C. M. and Cookson, W. O. (2001): Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits, Genomics, (vol. 72), No. 1, pp.15-20.. [16] Ober, C.; Leavitt, S. A.; Tsalenko, A.; Howard, T. D.; Hoki, D. M.; Daniel, R.; Newman, D. L.; Wu, X.; Parry, R.; Lester, L. A.; Solway, J.; Blumenthal, M.; King, R. A.; Xu, J.; Meyers, D. A.; Bleecker, E. R. and Cox, N. J. (2000): Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations, Am J Hum Genet, (vol. 66), No. 2, pp.517-26.. [17] Ober, C.; Tsalenko, A.; Willadsen, S.; Newman, D.; Daniel, R.; Wu, X.; Andal, J.; Hoki, D.; Schneider, D.; True, K.; Schou, C.; Parry, R. and Cox, N. (1999): Genome-wide screen for atopy susceptibility alleles in the Hutterites, Clin Exp Allergy, (vol. 29 Suppl 4), No. 2, pp.11-5.. [18] Noguchi, E.; Shibasaki, M.; Arinami, T.; Takeda, K.; Maki, T.; Miyamoto, T.; Kawashima, T.; Kobayashi, K. and Hamaguchi, H. (1997): Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population, Am J Respir Crit Care Med, (vol. 156), No. 5, pp.1390-3.. [19] Marsh, D. G.; Neely, J. D.; Breazeale, D. R.; Ghosh, B.; Freidhoff, L. R.; Ehrlich-Kautzky, E.; Schou, C.; Krishnaswamy, G. and Beaty, T. H. (1994): Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations, Science, (vol. 264), No. 5162, pp.1152-6.. [20] Deichmann, K.; Bardutzky, J.; Forster, J.; Heinzmann, A. and Kuehr, J. (1997): Common polymorphisms in the coding part of the IL4-receptor gene, Biochem Biophys Res Commun, (vol. 231), No. 3, pp.696-7.. [21] Rosenwasser, L. J.; Klemm, D. J.; Dresback, J. K.; Inamura, H.; Mascali, J. J.; Klinnert, M. and Borish, L. (1995): Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy, Clin Exp Allergy, (vol. 25 Suppl 2), No. 2-3, pp.74-8; discussion 95-6.. [22] Liu, X.; Nickel, R.; Beyer, K.; Wahn, U.; Ehrlich, E.; Freidhoff, L. R.; Bjorksten, B.; Beaty, T. H. and Huang, S. K. (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, (vol. 106), No. 1 Pt 1, pp.167-70.. [23] Heinzmann, A.; Mao, X. Q.; Akaiwa, M.; Kreomer, R. T.; Gao, P. S.; Ohshima, K.; Umeshita, R.; Abe, Y.; Braun, S.; Yamashita, T.; Roberts, M. H.; Sugimoto, R.; Arima, K.; Arinobu, Y.; Yu, B.; Kruse, S.; Enomoto, T.; Dake, Y.; Kawai, M.; Shimazu, S.; Sasaki, S.; Adra, C. N.; Kitaichi, M.; Inoue, H.; Yamauchi, K.; Tomichi, N.; Kurimoto, F.; Hamasaki, N.; Hopkin, J. M.; Izuhara, K.; Shirakawa, T. and Deichmann, K. A. (2000): Genetic variants of IL-13 signalling and human asthma and atopy, Hum Mol Genet, (vol. 9), No. 4, pp.549-59.. [24] Graves, P. E.; Kabesch, M.; Halonen, M.; Holberg, C. J.; Baldini, M.; Fritzsch, C.; Weiland, S. K.; Erickson, R. P.; von Mutius, E. and Martinez, F. D. (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, (vol. 105), No. 3, pp.506-13.. [25] Hershey, G. K.; Friedrich, M. F.; Esswein, L. A.; Thomas, M. L. and Chatila, T. A. (1997): The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor, N Engl J Med, (vol. 337), No. 24, pp.1720-5.. [26] Gerard, N.P.; Barnes, P. J. and al., et (1997): Asthma, Lippincott-Raven,

Philadelphia

. [27] Kikuchi, Y. and Kaplan, A. P. (2002): A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria, J Allergy Clin Immunol, (vol. 109), No. 1, pp.114-8.. [28] Gerard, N. P. and Gerard, C. (1991): The chemotactic receptor for human C5a anaphylatoxin, Nature, (vol. 349), No. 6310, pp.614-7.. [29] Gerard, N. P.; Hodges, M. K.; Drazen, J. M.; Weller, P. F. and Gerard, C. (1989): Characterization of a receptor for C5a anaphylatoxin on human eosinophils, J Biol Chem, (vol. 264), No. 3, pp.1760-6.. [30] Gasque, P.; Chan, P.; Fontaine, M.; Ischenko, A.; Lamacz, M.; Gotze, O. and Morgan, B. P. (1995): Identification and characterization of the complement C5a anaphylatoxin receptor on human astrocytes, J Immunol, (vol. 155), No. 10, pp.4882-9.. [31] Braun, M. and Davis, A. E., 3rd (1998): Cultured human glomerular mesangial cells express the C5a receptor, Kidney Int, (vol. 54), No. 5, pp.1542-9.. [32] Drouin, S. M.; Kildsgaard, J.; Haviland, J.; Zabner, J.; Jia, H. P.; McCray, P. B., Jr.; Tack, B. F. and Wetsel, R. A. (2001): Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma, J Immunol, (vol. 166), No. 3, pp.2025-32.. [33] Dempsey, P. W.; Allison, M. E.; Akkaraju, S.; Goodnow, C. C. and Fearon, D. T. (1996): C3d of complement as a molecular adjuvant: bridging innate and acquired immunity, Science, (vol. 271), No. 5247, pp.348-50.. [34] Karp, C. L.; Grupe, A.; Schadt, E.; Ewart, S. L.; Keane-Moore, M.; Cuomo, P. J.; Kohl, J.; Wahl, L.; Kuperman, D.; Germer, S.; Aud, D.; Peltz, G. and Wills-Karp, M. (2000): Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma, Nat Immunol, (vol. 1), No. 3, pp.221-6.. [35] Krug, N.; Tschernig, T.; Erpenbeck, V. J.; Hohlfeld, J. M. and Kohl, J. (2001): Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma, Am J Respir Crit Care Med, (vol. 164), No. 10 Pt 1, pp.1841-3.. [36] Laudes, I. J.; Chu, J. C.; Huber-Lang, M.; Guo, R. F.; Riedemann, N. C.; Sarma, J. V.; Mahdi, F.; Murphy, H. S.; Speyer, C.; Lu, K. T.; Lambris, J. D.; Zetoune, F. S. and Ward, P. A. (2002): Expression and function of C5a receptor in mouse microvascular endothelial cells, J Immunol, (vol. 169), No. 10, pp.5962-70.. [37] Hopken, U. E.; Lu, B.; Gerard, N. P. and Gerard, C. (1997): Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor, J Exp Med, (vol. 186), No. 5, pp.749-56.. [38] van der Pouw Kraan, T. C.; Boeije, L. C.; de Groot, E. R.; Stapel, S. O.; Snijders, A.; Kapsenberg, M. L.; van der Zee, J. S. and Aarden, L. A. (1997): Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma, J Immunol, (vol. 158), No. 11, pp.5560-5.. [39] Gerard, N. P.; Bao, L.; Xiao-Ping, H.; Eddy, R. L., Jr.; Shows, T. B. and Gerard, C. (1993): Human chemotaxis receptor genes cluster at 19q13.3-13.4. Characterization of the human C5a receptor gene, Biochemistry, (vol. 32), No. 5, pp.1243-50.. [40] Bao, L.; Gerard, N. P.; Eddy, R. L., Jr.; Shows, T. B. and Gerard, C. (1992): Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19, Genomics, (vol. 13), No. 2, pp.437-40.. [41] Ober, C.; Cox, N. J.; Abney, M.; Di Rienzo, A.; Lander, E. S.; Changyaleket, B.; Gidley, H.; Kurtz, B.; Lee, J.; Nance, M.; Pettersson, A.; Prescott, J.; Richardson, A.; Schlenker, E.; Summerhill, E.; Willadsen, S. and Parry, R. (1998): Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma, Hum Mol Genet, (vol. 7), No. 9, pp.1393-8.. [42] Ober, C.; Tsalenko, A.; Parry, R. and Cox, N. J. (2000): A second-generation genomewide screen for asthma-susceptibility alleles in a founder population, Am J Hum Genet, (vol. 67), No. 5, pp.1154-62.. [43] (1997): A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA), Nat Genet, (vol. 15), No. 4, pp.389-92.. [44] Dizier, M. H.; Besse-Schmittler, C.; Guilloud-Bataille, M.; Annesi-Maesano, I.; Boussaha, M.; Bousquet, J.; Charpin, D.; Degioanni, A.; Gormand, F.; Grimfeld, A.; Hochez, J.; Hyne, G.; Lockhart, A.; Luillier-Lacombe, M.; Matran, R.; Meunier, F.; Neukirch, F.; Pacheco, Y.; Parent, V.; Paty, E.; Pin, I.; Pison, C.; Scheinmann, P.; Thobie, N.; Vervloet, D. and Kauffmann, F. (2000): Genome screen for asthma and related phenotypes in the french EGEA study, Am J Respir Crit Care Med, (vol. 162), No. 5, pp.1812-8.. [45] Loiselle, J. and Wollin, A. (1993): Mucosal histamine elimination and its effect on acid secretion in rabbit gastric mucosa, Gastroenterology, (vol. 104), No. 4, pp.1013-20.. [46] Schwartz, J. C.; Arrang, J. M.; Garbarg, M.; Pollard, H. and Ruat, M. (1991): Histaminergic transmission in the mammalian brain, Physiol Rev, (vol. 71), No. 1, pp.1-51.. [47] Okinaga, S.; Ohrui, T.; Nakazawa, H.; Yamauchi, K.; Sakurai, E.; Watanabe, T.; Sekizawa, K. and Sasaki, H. (1995): The role of HMT (histamine N-methyltransferase) in airways: a review, Methods Find Exp Clin Pharmacol, (vol. 17), No. Suppl C, pp.16-20.. [48] Preuss, C. V.; Wood, T. C.; Szumlanski, C. L.; Raftogianis, R. B.; Otterness, D. M.; Girard, B.; Scott, M. C. and Weinshilboum, R. M. (1998): Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity, Mol Pharmacol, (vol. 53), No. 4, pp.708-17.. [49] Yan, L.; Galinsky, R. E.; Bernstein, J. A.; Liggett, S. B. and Weinshilboum, R. M. (2000): Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma, Pharmacogenetics, (vol. 10), No. 3, pp.261-6.. [50] Walker, C. and Virchow, J. C., Jr. (1993): T-cells and endothelial cells in asthma, Allergy, (vol. 48), No. 17 Suppl, pp.24-31; discussion 48-9.. [51] Holgate, S. T.; Hardy, C.; Robinson, C.; Agius, R. M. and Howarth, P. H. (1986): The mast cell as a primary effector cell in the pathogenesis of asthma, J Allergy Clin Immunol, (vol. 77), No. 2, pp.274-82.. [52] Dunnill, M. S.; Massarella, G. R. and Anderson, J. A. (1969): A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema, Thorax, (vol. 24), No. 2, pp.176-9.. [53] Takizawa, T. and Thurlbeck, W. M. (1971): Muscle and mucous gland size in the major bronchi of patients with chronic bronchitis, asthma, and asthmatic bronchitis, Am Rev Respir Dis, (vol. 104), No. 3, pp.331-6.. [54] Hogg, J. C. (1987): Varieties of airway narrowing in severe and fatal asthma, J Allergy Clin Immunol, (vol. 80), No. 3 Pt 2, pp.417-9.. [55] Brogan, T. D.; Ryley, H. C.; Allen, L. and Hutt, H. (1971): Relation between sputum sol phase composition and diagnosis in chronic chest diseases, Thorax, (vol. 26), No. 4, pp.418-23.. [56] Casale, T. B.; Wood, D.; Richerson, H. B.; Zehr, B.; Zavala, D. and Hunninghake, G. W. (1987): Direct evidence of a role for mast cells in the pathogenesis of antigen-induced bronchoconstriction, J Clin Invest, (vol. 80), No. 5, pp.1507-11.. [57] Leung, D. Y. and Bieber, T. (2003): Atopic dermatitis, Lancet, (vol. 361), No. 9352, pp.151-60.. [58] (1998): Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee, Lancet, (vol. 351), No. 9111, pp.1225-32.. [59] Taylor, B.; Wadsworth, J.; Wadsworth, M. and Peckham, C. (1984): Changes in the reported prevalence of childhood eczema since the 1939-45 war, Lancet, (vol. 2), No. 8414, pp.1255-7.. [60] Schafer, T.; Vieluf, D.; Behrendt, H.; Kramer, U. and Ring, J. (1996): Atopic eczema and other manifestations of atopy: results of a study in East and West Germany, Allergy, (vol. 51), No. 8, pp.532-9.. [61] Schultz Larsen, F.; Diepgen, T. and Svensson, A. (1996): The occurrence of atopic dermatitis in north Europe: an international questionnaire study, J Am Acad Dermatol, (vol. 34), No. 5 Pt 1, pp.760-4.. [62] Leung, D. Y.; Bhan, A. K.; Schneeberger, E. E. and Geha, R. S. (1983): Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies, J Allergy Clin Immunol, (vol. 71), No. 1 Pt 1, pp.47-56.. [63] Hamid, Q.; Naseer, T.; Minshall, E. M.; Song, Y. L.; Boguniewicz, M. and Leung, D. Y. (1996): In vivo expression of IL-12 and IL-13 in atopic dermatitis, J Allergy Clin Immunol, (vol. 98), No. 1, pp.225-31.. [64] Grewe, M.; Bruijnzeel-Koomen, C. A.; Schopf, E.; Thepen, T.; Langeveld-Wildschut, A. G.; Ruzicka, T. and Krutmann, J. (1998): A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis, Immunol Today, (vol. 19), No. 8, pp.359-61.. [65] Langeveld-Wildschut, E. G.; Riedl, H.; Thepen, T.; Bihari, I. C.; Bruijnzeel, P. L. and Bruijnzeel-Koomen, C. A. (2000): Modulation of the atopy patch test reaction by topical corticosteroids and tar, J Allergy Clin Immunol, (vol. 106), No. 4, pp.737-43.. [66] Nickoloff, B. J. and Naidu, Y. (1994): Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin, J Am Acad Dermatol, (vol. 30), No. 4, pp.535-46.. [67] Skoner, D. P. (2001): Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis, J Allergy Clin Immunol, (vol. 108), No. 1 Suppl, pp.S2-8.. [68] Meltzer, E. O. (1997): The prevalence and medical and economic impact of allergic rhinitis in the United States, J Allergy Clin Immunol, (vol. 99), No. 6 Pt 2, pp.S805-28.. [69] Wright, A. L.; Holberg, C. J.; Martinez, F. D.; Halonen, M.; Morgan, W. and Taussig, L. M. (1994): Epidemiology of physician-diagnosed allergic rhinitis in childhood, Pediatrics, (vol. 94), No. 6 Pt 1, pp.895-901.. [70] Rimpela, A. H.; Savonius, B.; Rimpela, M. K. and Haahtela, T. (1995): Asthma and allergic rhinitis among Finnish adolescents in 1977-1991, Scand J Soc Med, (vol. 23), No. 1, pp.60-5.. [71] Asher, M. I.; Keil, U.; Anderson, H. R.; Beasley, R.; Crane, J.; Martinez, F.; Mitchell, E. A.; Pearce, N.; Sibbald, B.; Stewart, A. W. and et al. (1995): International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods, Eur Respir J, (vol. 8), No. 3, pp.483-91.. [72] Barnes, K. C.; Fernandez-Caldas, E.; Trudeau, W. L.; Milne, D. E. and Brenner, R. J. (1997): Spetial and temporal distribution of house dust mite (Astigmata:Pyroglyphidae) allergens Der p 1 and Der f 1 in Barbadian homes, J Med Entomol, (vol. 34), No. 2, pp.212-8.. [73] Platt-Mills, T. A.; Sporik, R. B.; Chapman, M. D. and Heymann, P. W. (1995): The role of indoor allergens in asthma, Allergy, (vol. 50), No. 22 Suppl, pp.5-12.. [74] Devlin, B. and Risch, N. (1995): A comparison of linkage disequilibrium measures for fine-scale mapping, Genomics, (vol. 29), No. 2, pp.311-22.. [75] Liu, X.; Beaty, T. H.; Deindl, P.; Huang, S. K.; Lau, S.; Sommerfeld, C.; Fallin, M. D.; Kao, W. H.; Wahn, U. and Nickel, R. (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, (vol. 112), No. 2, pp.382-8.. [76] Schaid, D. J. and Rowland, C. M. (1999): Quantitative trait transmission disequilibrium test: allowance for missing parents, Genet Epidemiol, (vol. 17), No. Suppl 1, pp.S307-12.. [77] Wjst, M.; Heinrich, J.; Liu, P.; Dold, S.; Wassmer, G.; Merkel, G.; Huelsse, C. and Wichmann, H. E. (1994): Indoor factors and IgE levels in children, Allergy, (vol. 49), No. 9, pp.766-71.. [78] Atici, A.; Guneser, S.; Alparslan, N.; Antmen, B.; Yilmaz, M. and Onenli, N. (1994): Influence of smoke exposure on serum IgE levels of atopic patients, Acta Paediatr Jpn, (vol. 36), No. 3, pp.266-7.. [79] Kjellman, N. I. (1981): Effect of parental smoking on IgE levels in children, Lancet, (vol. 1), No. 8227, pp.993-4.. [80] Postma, D. S.; Bleecker, E. R.; Amelung, P. J.; Holroyd, K. J.; Xu, J.; Panhuysen, C. I.; Meyers, D. A. and Levitt, R. C. (1995): Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy, N Engl J Med, (vol. 333), No. 14, pp.894-900.. [81] Beyer, K.; Nickel, R.; Freidhoff, L.; Bjorksten, B.; Huang, S. K.; Barnes, K. C.; MacDonald, S.; Forster, J.; Zepp, F.; Wahn, V.; Beaty, T. H.; Marsh, D. G. and Wahn, U. (2000): Communications: association and linkage of atopic dermatitis with chromosome 13q12-14 and 5q31-33 markers, J Invest Dermatol, (vol. 115), No. 5, pp.906-8.. [82] Meyers, D. A.; Postma, D. S.; Panhuysen, C. I.; Xu, J.; Amelung, P. J.; Levitt, R. C. and Bleecker, E. R. (1994): Evidence for a locus regulating total serum IgE levels mapping to chromosome 5, Genomics, (vol. 23), No. 2, pp.464-70.. [83] Grunig, G.; Warnock, M.; Wakil, A. E.; Venkayya, R.; Brombacher, F.; Rennick, D. M.; Sheppard, D.; Mohrs, M.; Donaldson, D. D.; Locksley, R. M. and Corry, D. B. (1998): Requirement for IL-13 independently of IL-4 in experimental asthma, Science, (vol. 282), No. 5397, pp.2261-3.. [84] Wills-Karp, M.; Luyimbazi, J.; Xu, X.; Schofield, B.; Neben, T. Y.; Karp, C. L. and Donaldson, D. D. (1998): Interleukin-13: central mediator of allergic asthma, Science, (vol. 282), No. 5397, pp.2258-61.. [85] Coyle, A. J.; Le Gros, G.; Bertrand, C.; Tsuyuki, S.; Heusser, C. H.; Kopf, M. and Anderson, G. P. (1995): Interleukin-4 is required for the induction of lung Th2 mucosal immunity, Am J Respir Cell Mol Biol, (vol. 13), No. 1, pp.54-9.. [86] Weiland, S. K.; von Mutius, E.; Hirsch, T.; Duhme, H.; Fritzsch, C.; Werner, B.; Husing, A.; Stender, M.; Renz, H.; Leupold, W. and Keil, U. (1999): Prevalence of respiratory and atopic disorders among children in the East and West of Germany five years after unification, Eur Respir J, (vol. 14), No. 4, pp.862-70.. [87] Taussig, L. M.; Wright, A. L.; Morgan, W. J.; Harrison, H. R. and Ray, C. G. (1989): The Tucson Children's Respiratory Study. I. Design and implementation of a prospective study of acute and chronic respiratory illness in children, Am J Epidemiol, (vol. 129), No. 6, pp.1219-31.. [88] Zhu, Z.; Homer, R. J.; Wang, Z.; Chen, Q.; Geba, G. P.; Wang, J.; Zhang, Y. and Elias, J. A. (1999): Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production, J Clin Invest, (vol. 103), No. 6, pp.779-88.. [89] van der Pouw Kraan, T. C.; van Veen, A.; Boeije, L. C.; van Tuyl, S. A.; de Groot, E. R.; Stapel, S. O.; Bakker, A.; Verweij, C. L.; Aarden, L. A. and van der Zee, J. S. (1999): An IL-13 promoter polymorphism associated with increased risk of allergic asthma, Genes Immun, (vol. 1), No. 1, pp.61-5.. [90] Howard, T. D.; Whittaker, P. A.; Zaiman, A. L.; Koppelman, G. H.; Xu, J.; Hanley, M. T.; Meyers, D. A.; Postma, D. S. and Bleecker, E. R. (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, (vol. 25), No. 3, pp.377-84.. [91] Noguchi, E.; Shibasaki, M.; Arinami, T.; Takeda, K.; Yokouchi, Y.; Kawashima, T.; Yanagi, H.; Matsui, A. and Hamaguchi, H. (1998): Association of asthma and the interleukin-4 promoter gene in Japanese, Clin Exp Allergy, (vol. 28), No. 4, pp.449-53.. [92] Burchard, E. G.; Silverman, E. K.; Rosenwasser, L. J.; Borish, L.; Yandava, C.; Pillari, A.; Weiss, S. T.; Hasday, J.; Lilly, C. M.; Ford, J. G. and Drazen, J. M. (1999): Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma, Am J Respir Crit Care Med, (vol. 160), No. 3, pp.919-22.. [93] Walley, A. J. and Cookson, W. O. (1996): Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy, J Med Genet, (vol. 33), No. 8, pp.689-92.. [94] Sandford, A. J.; Chagani, T.; Zhu, S.; Weir, T. D.; Bai, T. R.; Spinelli, J. J.; Fitzgerald, J. M.; Behbehani, N. A.; Tan, W. C. and Pare, P. D. (2000): Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity, J Allergy Clin Immunol, (vol. 106), No. 1 Pt 1, pp.135-40.. [95] Kruse, S.; Japha, T.; Tedner, M.; Sparholt, S. H.; Forster, J.; Kuehr, J. and Deichmann, K. A. (1999): The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction, Immunology, (vol. 96), No. 3, pp.365-71.. [96] Risma, K. A.; Wang, N.; Andrews, R. P.; Cunningham, C. M.; Ericksen, M. B.; Bernstein, J. A.; Chakraborty, R. and Hershey, G. K. (2002): V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function, J Immunol, (vol. 169), No. 3, pp.1604-10.. [97] Kauppi, P.; Lindblad-Toh, K.; Sevon, P.; Toivonen, H. T.; Rioux, J. D.; Villapakkam, A.; Laitinen, L. A.; Hudson, T. J.; Kere, J. and Laitinen, T. (2001): A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma, Genomics, (vol. 77), No. 1-2, pp.35-42.. [98] Mitsuyasu, H.; Yanagihara, Y.; Mao, X. Q.; Gao, P. S.; Arinobu, Y.; Ihara, K.; Takabayashi, A.; Hara, T.; Enomoto, T.; Sasaki, S.; Kawai, M.; Hamasaki, N.; Shirakawa, T.; Hopkin, J. M. and Izuhara, K. (1999): Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis, J Immunol, (vol. 162), No. 3, pp.1227-31.. [99] Noguchi, E.; Shibasaki, M.; Arinami, T.; Takeda, K.; Yokouchi, Y.; Kobayashi, K.; Imoto, N.; Nakahara, S.; Matsui, A. and Hamaguchi, H. (1999): Lack of association of atopy/asthma and the interleukin-4 receptor alpha gene in Japanese, Clin Exp Allergy, (vol. 29), No. 2, pp.228-33.. [100] Gao, P. S.; Mao, X. Q.; Hopkin, J. M.; Adra, C. N.; Yang, X. and Shirakawa, T. (2000): Functional significance of polymorphisms of the interleukin-4 and interleukin-13 receptors in allergic disease, Clin Exp Allergy, (vol. 30), No. 12, pp.1672-5.. [101] Noguchi, E.; Shibasaki, M.; Arinami, T.; Takeda, K.; Yokouchi, Y.; Kobayashi, K.; Imoto, N.; Nakahara, S.; Matsui, A. and Hamaguchi, H. (1999): No association between atopy/asthma and the ILe50Val polymorphism of IL-4 receptor, Am J Respir Crit Care Med, (vol. 160), No. 1, pp.342-5.. [102] Laing, I. A.; Goldblatt, J.; Eber, E.; Hayden, C. M.; Rye, P. J.; Gibson, N. A.; Palmer, L. J.; Burton, P. R. and Le Souef, P. N. (1998): A polymorphism of the CC16 gene is associated with an increased risk of asthma, J Med Genet, (vol. 35), No. 6, pp.463-7.. [103] Le Souef, P. N.; Goldblatt, J. and Lynch, N. R. (2000): Evolutionary adaptation of inflammatory immune responses in human beings, Lancet, (vol. 356), No. 9225, pp.242-4.. [104] Martinson, J. J.; Chapman, N. H.; Rees, D. C.; Liu, Y. T. and Clegg, J. B. (1997): Global distribution of the CCR5 gene 32-basepair deletion, Nat Genet, (vol. 16), No. 1, pp.100-3.. [105] Nickel, R. G.; Casolaro, V.; Wahn, U.; Beyer, K.; Barnes, K. C.; Plunkett, B. S.; Freidhoff, L. R.; Sengler, C.; Plitt, J. R.; Schleimer, R. P.; Caraballo, L.; Naidu, R. P.; Levett, P. N.; Beaty, T. H. and Huang, S. K. (2000): Atopic dermatitis is associated with a functional mutation in the promoter of the C-C chemokine RANTES, J Immunol, (vol. 164), No. 3, pp.1612-6.. [106] Nickel, R. G.; Willadsen, S. A.; Freidhoff, L. R.; Huang, S. K.; Caraballo, L.; Naidu, R. P.; Levett, P.; Blumenthal, M.; Banks-Schlegel, S.; Bleecker, E.; Beaty, T.; Ober, C. and Barnes, K. C. (1999): Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides, Hum Immunol, (vol. 60), No. 8, pp.738-42.. [107] Gold, D. R.; Wypij, D.; Wang, X.; Speizer, F. E.; Pugh, M.; Ware, J. H.; Ferris, B. G., Jr. and Dockery, D. W. (1994): Gender- and race-specific effects of asthma and wheeze on level and growth of lung function in children in six U.S. cities, Am J Respir Crit Care Med, (vol. 149), No. 5, pp.1198-208.. [108] Sherman, C. B.; Tollerud, D. J.; Heffner, L. J.; Speizer, F. E. and Weiss, S. T. (1993): Airway responsiveness in young black and white women, Am Rev Respir Dis, (vol. 148), No. 1, pp.98-102.. [109] Lester, L. A.; Rich, S. S.; Blumenthal, M. N.; Togias, A.; Murphy, S.; Malveaux, F.; Miller, M. E.; Dunston, G. M.; Solway, J.; Wolf, R. L.; Samet, J. M.; Marsh, D. G.; Meyers, D. A.; Ober, C. and Bleecker, E. R. (2001): Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma, J Allergy Clin Immunol, (vol. 108), No. 3, pp.357-62..