SciELO - Scientific Electronic Library Online

 
vol.12 número6Determinação da neopterina e de defesas antioxidantes na asma de evolução arrastadaAsma, polipose nasal e intolerância à aspirina: Uma tríade a recordar índice de autoresíndice de assuntosPesquisa de artigos
Home Pagelista alfabética de periódicos  

Serviços Personalizados

Journal

Artigo

Indicadores

Links relacionados

  • Não possue artigos similaresSimilares em SciELO

Compartilhar


Revista Portuguesa de Pneumologia

versão impressa ISSN 0873-2159

Rev Port Pneumol v.12 n.6 Lisboa nov. 2006

 

Os factores genéticos da asma

Asthma genetic factors

 

Paula Alexandra Videira 1

Luís Miguel Borrego 2

Hélder Trindade 3

 

Resumo

A asma brônquica é uma doença inflamatória crónica das vias aéreas, de prevalência crescente, particularmente na infância, sendo considerado um importante problema de saúde pública. É reconhecidamente uma doença de transmissão familiar, sendo um desafio a descrição e potencial identificação dos genes envolvidos na sua génese. Pretende-se com o presente artigo de revisão explicitar exaustivamente os genes associados a esta patologia, bem como esclarecer os métodos laboratoriais que permitem a sua identificação.

Palavras-chave: Asma, susceptibilidade genética, genome wide screen, estudos de associação, farmacogenética.

 

Abstract

Asthma is a chronic inflammatory airways disease, with a rising prevalence, particularly in childhood, and is considered an important Public Health problem. It’s familial transmission is recognised, while the description and identification of the genes implicated in this disease are a challenge. In this revision paper the authors give a comprehensive explanation of the associated genes as well as the laboratorial methods that allow their identification.

Key-words: Asthma, genetic susceptibility, genome wide screen, association studies, pharmacogenetics.

 

Texto completo disponível apenas em PDF.

Full text only available in PDF format.

 

Bibliografia

1. Nunes C, Ladeira S, Rosado Pinto J. Definição, epidemiologia e classificação da asma na criança. In A criança asmática no mundo da alergia. Rosado Pinto J, Morais de Almeida M (Eds.) Lisboa 2003; 35-55.        [ Links ]

2. National Institutes of Health NHLBI: Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, Md: National Institutes of Health Publication 02-3659; 2002.

3. Holgate ST. The epidemic of allergy and asthma. Nature 1999; 402:B2-4.

4. Koppelman GH, Los H, Postma DS. Genetic and environment in asthma: the answer of twin studies. Eur Respir J 1999; 13:2-4.

5. Black JA, Lewis HE, Thacker CK, Thould AK. Tristan da Cunha: General Medical Investigations. Br Med J 1963; 5364:1013-1024.

6. Blumenthal MN. The role of genetics in the development of asthma and atopy. Curr Opin Allergy Clin Immunol 2005; 5:141-145.

7. Lind DL, Choudhry S, Ung N, Ziv E, Avila PC, Salari K et al. ADAM33 is not associated with asthma in Puerto Rican or Mexican populations. Am J Respir Crit Care Med 2003; 168:1312-1316.

8. Morton NE. Logarithm of odds (lods) for linkage in complex inheritance. Proc Natl Acad Sci U S A 1996; 93:3471-3476.

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

10. Lee WC. Searching for disease-susceptibility loci by testing for Hardy-Weinberg disequilibrium in a gene bank of affected individuals. Am J Epidemiol 2003; 158:397-400.

11. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11:241-247.

12. Cookson WO. Asthma genetics. Chest 2002;121:7S-13S.

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

14. Howard TD, Meyers DA, Bleecker ER. Mapping susceptibility genes for allergic diseases. Chest 2003; 123:363S-368S.

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

16. Gohlke H, Illig T, Bahnweg M, Klopp N, Andre E, Altmuller J, Herbon N, Werner M, et al. Association of the interleukin-1 receptor antagonist gene with asthma. Am J Respir Crit Care Med 2004; 169:1217-1223.

17. Kabesch M, Carr D, Weiland SK, von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clin Exp Allergy 2004; 34:340-345.

18. Jongepier H, Koppelman GH, Nolte IM, Bruinenberg M, Bleecker ER, Meyers DA, te Meerman GJ, Postma DS. Polymorphisms in SPINK5 are not associated with asthma in a Dutch population. J Allergy Clin Immunol 2005; 115:486-492.

19. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R, Edser P, Bhattacharyya S, 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.

20. Melen E, Bruce S, Doekes G, Kabesch M, Laitinen T, Lauener R, Lindgren CM, Riedler J, et al. Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma. Am J Respir Crit Care Med 2005; 171:1089-1095.

21. Kormann MS, Carr D, Klopp N, Illig T, Leupold W, Fritzsch C, Weiland SK, von Mutius E, et al. G-Proteincoupled receptor polymorphisms are associated with asthma in a large German population. Am J Respir Crit Care Med 2005; 171:1358-1362.

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

23. Shin HD, Park KS, Park CS. Lack of association of GPRA (G protein-coupled receptor for asthma susceptibility) haplotypes with high serum IgE or asthma in a Korean population. J Allergy Clin Immunol 2004; 114:1226-1227.

24. Veal CD, Reynolds NJ, Meggitt SJ, Allen MH, Lindgren CM, Kere J, Trembath RC, Barker JN. Absence of association between asthma and high serum immunoglobulin E associated GPRA haplotypes and adult atopic dermatitis. J Invest Dermatol 2005; 125:399-401.

25. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996; 380:630-633.

26. Gao PS, Mao XQ, Roberts MH, Arinobu Y, Akaiwa M, Enomoto T, Dake Y, Kawai M, et al. Variants of STAT6 (signal transducer and activator of transcription 6) in atopic asthma. J Med Genet 2000; 37:380-382.

27. Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, Tokuyama K, Morikawa A. Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 2001; 31:1509-1514.

28. Tamura K, Suzuki M, Arakawa H, Tokuyama K, Morikawa A. Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol 2003; 131:33-38.

29. Gao PS, Heller NM, Walker W, Chen CH, Moller M, Plunkett B, Roberts MH, Schleimer RP, et al. Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro. J Med Genet 2004; 41:535-539.

30. Pykalainen M, Kinos R, Valkonen S, Rydman P, Kilpelainen M, Laitinen LA, Karjalainen J, Nieminen M, et al. Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes. J Allergy Clin Immunol 2005; 115:80-87.

31. Weidinger S, Klopp N, Wagenpfeil S, Rummler L, Schedel M, Kabesch M, Schafer T, Darsow U, et al. Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults. J Med Genet 2004; 41:658-663.

32. Schedel M, Carr D, Klopp N, Woitsch B, Illig T, Stachel D, Schmid I, Fritzsch C, et al. A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels. J Allergy Clin Immunol 2004; 114:1100-1105.

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

34. Xu J, Meyers DA, Ober C, Blumenthal MN, Mellen B, Barnes KC, King RA, Lester LA, et al. Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet 2001; 68:1437-1446.

35. Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, Park CS, Hong SJ, et al. ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics. Clin Exp Allergy 2004; 34:860-865.

36. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, Koppelman GH, Zheng SL, Meyers DA, et al. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 2004; 34:757-760.

37. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am J Respir Crit Care Med 2005; 172:329-333.

38. Werner M, Herbon N, Gohlke H, Altmuller J, Knapp M, Heinrich J, Wjst M. Asthma is associated with single-nucleotide polymorphisms in ADAM33. Clin Exp Allergy 2004; 34:26-31.

39. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST, Woodcock A, Ollier WE, et al. Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am J Respir Crit Care Med 2005; 172:55-60.

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

41. Holgate ST, Davies DE, Powell RM, Holloway JW. ADAM33: a newly identified protease involved in airway remodelling. Pulm Pharmacol Ther 2006; 19:3-11.

42. Raby BA, Silverman EK, Kwiatkowski DJ, Lange C, Lazarus R, Weiss ST. ADAM33 polymorphisms and phenotype associations in childhood asthma. J Allergy Clin Immunol 2004; 113:1071-1078.

43. Howard TD, Postma DS, Jongepier H, Moore WC, Koppelman GH, Zheng SL, Xu J, Bleecker ER, et al. Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol 2003; 112:717-722.

44. Shapiro SD, Owen CA. ADAM-33 surfaces as an asthma gene. N Engl J Med 2002; 347:936-938.

45. Umland SP, Garlisi CG, Shah H, Wan Y, Zou J, Devito KE, Huang WM, Gustafson EL, Ralston R. Human ADAM33 messenger RNA expression profile and posttranscriptional regulation. Am J Respir Cell Mol Biol 2003; 29:571-582.

46. Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C, Kuldanek S, Donfack J, 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.

47. Hviid TV. HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update 2006; 12:209-232.

48. Rizzo R, Mapp CE, Melchiorri L, Maestrelli P, Visentin A, Ferretti S, Bononi I, Miotto D, et al. Defective production of soluble HLA-G molecules by peripheral blood monocytes in patients with asthma. J Allergy Clin Immunol 2005; 115:508-513.

49. Temple R, Allen E, Fordham J, Phipps S, Schneider HC, Lindauer K, Hayes I, Lockey J, et al. Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes. Am J Respir Cell Mol Biol 2001; 25:425-433.

50. Laprise C, Sladek R, Ponton A, Bernier MC, Hudson TJ, Laviolette M. Functional classes of bronchial mucosa genes that are differentially expressed in asthma. BMC Genomics 2004; 5:21.

51. Hansel NN, Hilmer SC, Georas SN, Cope LM, Guo J, Irizarry RA, Diette GB. Oligonucleotide-microarray analysis of peripheral-blood lymphocytes in severe asthma. J Lab Clin Med 2005; 145:263-274.

52. Guajardo JR, Schleifer KW, Daines MO, Ruddy RM, Aronow BJ, Wills-Karp M, Hershey GK. Altered gene expression profiles in nasal respiratory epithelium reflect stable versus acute childhood asthma. J Allergy Clin Immunol 2005; 115:243-251.

53. Lilly CM, Tateno H, Oguma T, Israel E, Sonna LA. Effects of allergen challenge on airway epithelial cell gene expression. Am J Respir Crit Care Med 2005; 171:579-586.

54. Yuyama N, Davies DE, Akaiwa M, Matsui K, Hamasaki Y, Suminami Y, Yoshida NL, Maeda M, et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine 2002; 19:287-296.

55. Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, Muntel EE, Witte DP, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 2003; 111:1863-1874.

56. Zou J, Young S, Zhu F, Gheyas F, Skeans S, Wan Y, Wang L, Ding W, et al. Microarray profile of differentially expressed genes in a monkey model of allergic asthma. Genome Biol 2002, 3:research0020.

57. Benson M, Olsson M, Rudemo M, Wennergren G, Cardell LO. Pros and cons of microarray technology in allergy research. Clin Exp Allergy 2004; 34:1001-1006.

58. D’Ambrosio C, Gatta L, Bonini S. The future of microarray technology: networking the genome search. Allergy 2005; 60:1219-1226.

59. Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM, Fahy JV, Erle DJ. Dissecting asthma using focused transgenic modeling and functional genomics. J Allergy Clin Immunol 2005; 116:305-311.

60. Sandford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, Fitzgerald JM, Behbehani NA, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000; 106:135-140.

61. Noguchi E, Nukaga-Nishio Y, Jian Z, Yokouchi Y, Kamioka M, Yamakawa-Kobayashi K, Hamaguchi H, Matsui A, et al. Haplotypes of the 5' region of the IL-4 gene and SNPs in the intergene sequence between the IL-4 and IL-13 genes are associated with atopic asthma. Hum Immunol 2001; 62:1251-1257.

62. Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, Bleecker ER. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 2002; 70:230-236.

63. Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, Newman DL, Wu X, 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.

64. Zhu S, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WT, Pare PD, et al. Polymorphisms of the IL-4, TNF-alpha, and Fcepsilon RIbeta genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000; 161:1655-1659.

65. Suzuki I, Hizawa N, Yamaguchi E, Kawakami Y. Association between a C+33T polymorphism in the IL-4 promoter region and total serum IgE levels. Clin Exp Allergy 2000; 30:1746-1749.

66. Howard TD, Whittaker PA, Zaiman AL, Koppelman GH, Xu J, Hanley MT, Meyers DA, Postma DS, 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 2001; 25:377-384.

67. Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima K, Umeshita R, Abe Y, et al. Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 2000; 9:549-559.

68. Graves PE, Kabesch M, Halonen M, Holberg CJ, Baldini M, Fritzsch C, Weiland SK, Erickson RP, 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 2000; 105:506-513.

69. Basehore MJ, Howard TD, Lange LA, Moore WC, Hawkins GA, Marshik PL, Harkins MS, Meyers DA, 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 2004; 114:80-87.

70. Meyers DA, Postma DS, Stine OC, Koppelman GH, Ampleford EJ, Jongepier H, Howard TD, Bleecker ER. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J Allergy Clin Immunol 2005; 115:1169-1175.

71. 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.

72. Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, et al. Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998; 7:1393-1398.

73. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev 2004; 202:175-190.

74. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science 2003; 300:1527-1528.

75. van der Pouw Kraan TC, van Veen A, Boeije LC, van Tuyl SA, de Groot ER, Stapel SO, Bakker A, Verweij CL, et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1999; 1:61-65.

76. Arima K, Sato K, Tanaka G, Kanaji S, Terada T, Honjo E, Kuroki R, Matsuo Y, et al. Characterization of the interaction between interleukin-13 and interleukin-13 receptors. J Biol Chem 2005; 280:24915-24922.

77. Arima K, Umeshita-Suyama R, Sakata Y, Akaiwa M, Mao XQ, Enomoto T, Dake Y, Shimazu S, et al. Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma. J Allergy Clin Immunol 2002; 109:980-987.

78. Walley AJ, Cookson WO. Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy. J Med Genet 1996; 33:689-692.

79. Nagarkatti R, Kumar R, Sharma SK, Ghosh B. Association of IL4 gene polymorphisms with asthma in North Indians. Int Arch Allergy Immunol 2004; 134:206-212.

80. Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today 2000; 21:60-64.

81. Faffe DS, Whitehead T, Moore PE, Baraldo S, Flynt L, Bourgeois K, Panettieri RA, Shore SA. IL--13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype. Am J Physiol Lung Cell Mol Physiol 2003; 285:L907-914.

82. Mitsuyasu H, Yanagihara Y, Mao XQ, Gao PS, Arinobu Y, Ihara K, Takabayashi A, Hara T, et al. Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis. J Immunol 1999; 162:1227-1231.

83. Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kobayashi K, Imoto N, Nakahara S, et al. No association between atopy/asthma and the ILe50Val polymorphism of IL-4 receptor. Am J Respir Crit Care Med 1999; 160:342-345.

84. Liu X, Beaty TH, Deindl P, Huang SK, Lau S, Sommerfeld C, Fallin MD, Kao WH, et al. 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 2003; 112:382-388.

85. Palmer LJ, Rye PJ, Gibson NA, Moffatt MF, Goldblatt J, Burton PR, Cookson WO, Lesouef PN. Association of FcepsilonR1-beta polymorphisms with asthma and associated traits in Australian asthmatic families. Clin Exp Allergy 1999; 29:1555-1562.

86. Zhang X, Zhang W, Qiu D, Sandford A, Tan WC. The E237G polymorphism of the high-affinity IgE receptor beta chain and asthma. Ann Allergy Asthma Immunol 2004; 93:499-503.

87. Korzycka-Zaborowska B, Hopkin JM, Gorski P. Genetic variants of FcepsilonRIbeta and Il-4 and atopy in a Polish population. Allergol Immunopathol (Madr) 2004; 32:53-58.

88. Lee YL, Hsiue TR, Lee YC, Lin YC, Guo YL. The association between glutathione S-transferase P1, M1 polymorphisms and asthma in Taiwanese schoolchildren. Chest 2005; 128:1156-1162.

89. Lee YL, Lin YC, Lee YC, Wang JY, Hsiue TR, Guo YL. Glutathione S-transferase P1 gene polymorphism and air pollution as interactive risk factors for childhood asthma. Clin Exp Allergy 2004; 34:1707-1713.

90. Aynacioglu AS, Nacak M, Filiz A, Ekinci E, Roots I. Protective role of glutathione S-transferase P1 (GSTP1) Val105Val genotype in patients with bronchial asthma. Br J Clin Pharmacol 2004; 57:213-217.

91. Hill MR, James AL, Faux JA, Ryan G, Hopkin JM, le Souef P, Musk AW, Cookson WO. Fc epsilon RI-beta olymorphism and risk of atopy in a general population sample. BMJ 1995; 311:776-779.

92. Child F, Lenney W, Clayton S, Davies S, Jones PW, Alldersea JE, Strange RC, Fryer AA. The association of maternal but not paternal genetic variation in GSTP1 with asthma phenotypes in children. Respir Med 2003; 97:1247-1256.

93. Brasch-Andersen C, Christiansen L, Tan Q, Haagerup A, Vestbo J, Kruse TA. Possible gene dosage effect of glutathione-S-transferases on atopic asthma: using real-time PCR for quantification of GSTM1 and GSTT1 gene copy numbers. Hum Mutat 2004; 24:208-214.

94. Moffatt MF, James A, Ryan G, Musk AW, Cookson WO. Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 1999; 54:757-761.

95. Randolph AG, Lange C, Silverman EK, Lazarus R, Weiss ST. Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthmarelated phenotypes. Am J Respir Crit Care Med 2005; 172:687-692.

96. Chang HS, Kim JS, Lee JH, Cho JI, Rhim TY, Uh ST, Park BL, Chung IY, et al. A single nucleotide polymorphism on the promoter of eotaxin1 associates with its mRNA expression and asthma phenotypes. J Immunol 2005; 174:1525-1531.

97. Fukunaga K, Asano K, Mao XQ, Gao PS, Roberts MH, Oguma T, Shiomi T, Kanazawa M, et al. Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics. Eur Respir J 2001; 17:59-63.

98. Tantisira KG, Weiss ST. The pharmacogenetics of asthma: an update. Curr Opin Mol Ther 2005; 7:209-217.

99. Kay LJ, Peachell PT. Mast cell beta2-adrenoceptors. Chem Immunol Allergy 2005; 87:145-153.

100. Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharmacogenetics of asthma. Am J Respir Crit Care Med 2002; 165:861-866.

101. Liggett SB. The pharmacogenetics of beta2-adrenergic receptors: relevance to asthma. J Allergy Clin Immunol 2000; 105:S487-492.

102. Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:1635-1641.

103. Green SA, Turki J, Innis M, Liggett SB. Aminoterminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33:9414-9419.

104. Barnes KC. Atopy and asthma genes – where do we stand? Allergy 2000; 55:803-817.

105. Liggett SB. Pharmacogenetics of beta-1- and beta-2-adrenergic receptors. Pharmacology 2000; 61:167-173.

106. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 2000; 97:10483-10488.

107. Leung DY, Martin RJ, Szefler SJ, Sher ER, Ying S, Kay AB, Hamid Q. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 1995; 181:33-40.

108. Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, Chrousos GP, Klemm DJ. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 1997; 186:1567-1574.

109. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, Liggett SB, Gelfand EW, et al.. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 2004; 13:1353-1359.

110. Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999; 22:168-170.

111. Yoshikawa K, Matsui E, Kaneko H, Fukao T, Inoue R, Teramoto T, Shinoda S, Fukutomi O, et al. A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases. Int J Mol Med 2005; 16:827-831.

112. Ramires R, Caiaffa MF, Tursi A, Haeggstrom JZ, Macchia L. Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast. Biochem Biophys Res Commun 2004; 324:815-821.

113. Sasaki Y, Ihara K, Ahmed S, Yamawaki K, Kusuhara K, Nakayama H, Nishima S, Hara T. Lack of association between atopic asthma and polymorphisms of the histamine H1 receptor, histamine H2 receptor, and histamine N-methyltransferase genes. Immunogenetics 2000; 51:238-240.

114. Yan L, Galinsky RE, Bernstein JA, Liggett SB, Weinshilboum RM. Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma. Pharmacogenetics 2000; 10:261-266.

115. Sharma S, Mann D, Singh TP, Ghosh B. Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population. J Hum Genet 2005; 50:611-617.

116. Deindl P, Peri-Jerkan S, Deichmann K, Niggemann B, Lau S, Sommerfeld C, Sengler C, Muller S, et al. No association of histamine- N-methyltransferase polymorphism with asthma or bronchial hyperresponsiveness in two German pediatric populations. Pediatr Allergy Immunol 2005; 16:40-42.

117. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004; 364:1505-1512.

118. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, Faux JA, Ryan GF, et al. A genomewide search for quantitative trait loci underlying asthma. Nature 1996; 383:247-250.

119. Hizawa N, Freidhoff LR, Chiu YF, Ehrlich E, Luehr CA, Anderson JL, Duffy DL, Dunston GM, et al. Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study on the Genetics of Asthma (CSGA). J Allergy Clin Immunol 1998; 102:436-442.

120. Wjst M, Fischer G, Immervoll T, Jung M, Saar K, Rueschendorf F, Reis A, Ulbrecht M, et al. A genomewide search for linkage to asthma. German Asthma Genetics Group. Genomics 1999; 58:1-8.

121. Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J, Charpin D, Degioanni A, et al. Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 2000; 162:1812-1818.

122. Yokouchi Y, Nukaga Y, Shibasaki M, Noguchi E, Kimura K, Ito S, Nishihara M, Yamakawa-Kobayashi K, et al. Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 2000; 66:152-160.

123. Ober C, Tsalenko A, Parry R, Cox NJ. A secondgeneration genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 2000, 67:1154-1162.

124. Xu X, Fang Z, Wang B, Chen C, Guang W, Jin Y, Yang J, Lewitzky S, et al. A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet 2001; 69:1271-1277.

125. Laitinen T, Daly MJ, Rioux JD, Kauppi P, Laprise C, Petays T, Green T, Cargill M, et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet 2001; 28:87-91.

126. Hakonarson H, Bjornsdottir US, Halapi E, Palsson S, Adalsteinsdottir E, Gislason D, Finnbogason G, Gislason T, et al. A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet 2002; 71:483-491.

127. Haagerup A, Bjerke T, Schiotz PO, Binderup HG, Dahl R, Kruse TA. Asthma and atopy – a total genome scan for susceptibility genes. Allergy 2002; 57:680-686.

128. Postma DS, Meyers DA, Jongepier H, Howard TD, Koppelman GH, Bleecker ER. Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 200; 172:446-452.

129. Wang JY, Lin CG, Bey MS, Wang L, Lin FY, Huang L, Wu LS. Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers. J Hum Genet 2005; 50:249-258.

 

1 Assistente Convidada Doutorada,

2 Assistente Convidado. Assistente Hospitalar de Imunoalergologia do Hospital Dona Estefânia

3 Professor Associado Convidado com Agregação

 

Faculdade de Ciências Médicas, Departamento de Imunologia

Universidade Nova de Lisboa

Campo dos Mártires da Pátria, n.º 130

1169-056 Lisboa

Tel: 351-218803045/ 218853000

Fax: 218853480

 

Recebido para publicação/received for publication: 06.06.28

Aceite para publicação/accepted for publication: 06.07.30