Present status on the genetic studies of asthma

Current Opinion in Immunology

Volumn 14, Issue 6, 2002, Pages 709-717

  Hoffjan, Sabine ^a   Ober, Carole ^a  

^a UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 13; INTERLEUKIN 13 RECEPTOR; INTERLEUKIN 4; IL13RA1 PROTEIN, HUMAN; IL13RA1 PROTEIN, MOUSE; INTERLEUKIN 13 RECEPTOR ALPHA1; INTERLEUKIN 4 RECEPTOR; INTERLEUKIN RECEPTOR; STAT6 PROTEIN; STAT6 PROTEIN, HUMAN; STAT6 PROTEIN, MOUSE; TRANSACTIVATOR PROTEIN;

ASTHMA; GENE SEQUENCE; GENETIC CODE; GENETIC CORRELATION; GENETIC TRANSCRIPTION; GENOME; NONHUMAN; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CHROMOSOME MAP; GENETIC HETEROGENEITY; GENETIC VARIABILITY; GENETICS; HUMAN; MOUSE; PHYSIOLOGY;

ANIMALS; ASTHMA; CHROMOSOME MAPPING; GENETIC HETEROGENEITY; HUMANS; INTERLEUKIN-13; INTERLEUKIN-13 RECEPTOR ALPHA1 SUBUNIT; INTERLEUKIN-4; MICE; RECEPTORS, INTERLEUKIN; RECEPTORS, INTERLEUKIN-13; RECEPTORS, INTERLEUKIN-4; SIGNAL TRANSDUCTION; STAT6 TRANSCRIPTION FACTOR; TRANS-ACTIVATORS; VARIATION (GENETICS);

EID: 0036888556     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(02)00393-X     Document Type: Review

References (83)

1. Asher M.I., Keil U., Anderson H.R., Beasley R., Crane J., Martinez F., Mitchell E.A., Pearce N., Sibbald B., Stewart A.W., et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 8:1995;483-491.
2. Beasley R. The burden of asthma with specific reference to the United States. J Allergy Clin Immunol. 109:2002;S482-S489.
3. Nolte H., Backer V., Porsbjerg C. Environmental factors as a cause for the increase in allergic disease. Ann Allergy Asthma Immunol. 87:2001;7-11.
4. Cookson W. The alliance of genes and environment in asthma and allergy. Nature. 402:1999;B5-B11.
5. Daniels S.E., Bhattacharrya S., James A., Leaves N.I., Young A., Hill M.R., Faux J.A., Ryan G.F., le Souef P.N., Lathrop G.M., et al. A genome-wide search for quantitative trait loci underlying asthma. Nature. 383:1996;247-250.
6. Xu J., Meyers D.A., Ober C., Blumenthal M.N., Mellen B., Barnes K.C., King R.A., Lester L.A., Howard T.D., Solway J., 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. 68:2001;1437-1446. This is an important study with the first genome-wide screen for asthma that considers gene-gene interactions.
7. Mathias R.A., Freidhoff L.R., Blumenthal M.N., Meyers D.A., Lester L., King R., Xu J.F., Solway J., Barnes K.C., Pierce J., et al. Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families. Genet Epidemiol. 20:2001;340-355.
8. 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. 67:2000;1154-1162.
9. Wjst M., Fischer G., Immervoll T., Jung M., Saar K., Rueschendorf F., Reis A., Ulbrecht M., Gomolka M., Weiss E.H., et al. A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics. 58:1999;1-8.
10. Dizier M.H., Besse-Schmittler C., Guilloud-Bataille M., Annesi-Maesano I., Boussaha M., Bousquet J., Charpin D., Degioanni A., Gormand F., Grimfeld A., et al. Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med. 162:2000;1812-1818.
11. Xu J., Postma D.S., Howard T.D., Koppelman G.H., Zheng S.L., Stine O.C., Bleecker E.R., Meyers D.A. Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet. 67:2000;1163-1173.
12. Koppelman G.H., Stine O.C., Xu J., Howard T.D., Zheng S.L., Kauffman H.F., Bleecker E.R., Meyers D.A., Postma D.S. Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol. 109:2002;498-506.
13. Yokouchi Y., Nukaga Y., Shibasaki M., Noguchi E., Kimura K., Ito S., Nishihara M., Yamakawa-Kobayashi K., Takeda K., Imoto N., 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. 66:2000;152-160.
14. Yokouchi Y., Shibasaki M., Noguchi E., Nakayama J., Ohtsuki T., Kamioka M., Yamakawa-Kobayashi K., Ito S., Takeda K., Ichikawa K., et al. A genome-wide linkage analysis of orchard grass-sensitive childhood seasonal allergic rhinitis in Japanese families. Genes Immun. 3:2002;9-13.
15. Xu X., Fang Z., Wang B., Chen C., Guang W., Jin Y., Yang J., Lewitzky S., Aelony A., Parker A., et al. A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet. 69:2001;1271-1277.
16. Laitinen T., Daly M.J., Rioux J.D., Kauppi P., Laprise C., Petays T., Green T., Cargill M., Haahtela T., Lander E.S., et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet. 28:2001;87-91.
17. Haagerup A., Bjerke T., Schoitz P.O., Binderup H.G., Dahl R., Kruse T.A. Allergic rhinitis-a total genome-scan for susceptibility genes suggests a locus on chromosome 4q24-q27. Eur J Hum Genet. 9:2001;945-952.
18. Wjst M., Immervoll T. An internet linkage and mutation database for the complex phenotype asthma. Bioinformatics. 14:1998;827-828.
19. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 11:1995;241-247.
20. De Sanctis G.T., Merchant M., Beier D.R., Dredge R.D., Grobholz J.K., Martin T.R., Lander E.S., Drazen J.M. Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nat Genet. 11:1995;150-154.
21. De Sanctis G.T., Singer J.B., Jiao A., Yandava C.N., Lee Y.H., Haynes T.C., Lander E.S., Beier D.R., Drazen J.M. Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice. Am J Physiol. 277:1999;L1118-L1123.
22. Ewart S.L., Kuperman D., Schadt E., Tankersley C., Grupe A., Shubitowski D.M., Peltz G., Wills-Karp M. Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol. 23:2000;537-545.
23. Zhang Y., Lefort J., Kearsey V., Lapa e Silva J.R., Cookson W.O., Vargaftig B.B. A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma. Hum Mol Genet. 8:1999;601-605.
24. Hakonarson H., Wjst M. Current concepts on the genetics of asthma. Curr Opin Pediatr. 13:2001;267-277. This is an excellent review highlighting the results of all published genome-wide screens as well as recent association studies on asthma and atopy. The authors specifically address the difficulty in interpreting statistical results in the mapping of complex disorders.
25. Barnes K.C. Atopy and asthma genes-where do we stand? Allergy. 55:2000;803-817.
26. Cookson W.O. Asthma genetics. Chest. 121:2002;7S-13S.
27. Ober C., Moffatt M.F. Contributing factors to the pathobiology. The genetics of asthma. Clin Chest Med. 21:2000;245-261.
28. Wills-Karp M., Luyimbazi J., Xu X., Schofield B., Neben T.Y., Karp C.L., Donaldson D.D. Interleukin-13: central mediator of allergic asthma. Science. 282:1998;2258-2261.
29. Punnonen J., Yssel H., de Vries J.E. The relative contribution of IL-4 and IL-13 to human IgE synthesis induced by activated CD4+ or CD8+ T cells. J Allergy Clin Immunol. 100:1997;792-801.
30. Marsh D.G., Neely J.D., Breazeale D.R., Ghosh B., Freidhoff L.R., Ehrlich-Kautzky E., Schou C., Krishnaswamy G., Beaty T.H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 264:1994;1152-1156.
31. Meyers D.A., Postma D.S., Panhuysen C.I., Xu J., Amelung P.J., Levitt R.C., Bleecker E.R. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics. 23:1994;464-470.
32. Walley A.J., Wiltshire S., Ellis C.M., Cookson W.O. Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits. Genomics. 72:2001;15-20.
33. Holberg C.J., Halonen M., Solomon S., Graves P.E., Baldini M., Erickson R.P., Martinez F.D. Factor analysis of asthma and atopy traits shows 2 major components, one of which is linked to markers on chromosome 5q. J Allergy Clin Immunol. 108:2001;772-780.
34. Symula D.J., Frazer K.A., Ueda Y., Denefle P., Stevens M.E., Wang Z.E., Locksley R., Rubin E.M. Functional screening of an asthma QTL in YAC transgenic mice. Nat Genet. 23:1999;241-244.
35. Rosenwasser L.J., Klemm D.J., Dresback J.K., Inamura H., Mascali J.J., Klinnert M., Borish L. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy. 25:1995;74-78.
36. Shirakawa I., Deichmann K.A., Izuhara I., Mao I., Adra C.N., Hopkin J.M. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today. 21:2000;60-64.
37. 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., et al. Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med. 160:1999;919-922.
38. 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., Pare P.D. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol. 106:2000;135-140.
39. Takabayashi A., Ihara K., Sasaki Y., Suzuki Y., Nishima S., Izuhara K., Hamasaki N., Hara T. Childhood atopic asthma: positive association with a polymorphism of IL- 4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene. Exp Clin Immunogenet. 17:2000;63-70.
40. Hijazi Z., Haider M.Z. Interleukin-4 gene promoter polymorphism [C590T] and asthma in Kuwaiti Arabs. Int Arch Allergy Immunol. 122:2000;190-194.
41. Zhu S., Chan-Yeung M., Becker A.B., Dimich-Ward H., Ferguson A.C., Manfreda J., Watson W.T., Pare P.D., Sandford A.J. 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. 161:2000;1655-1659.
42. Elliott K., Fitzpatrick E., Hill D., Brown J., Adams S., Chee P., Stewart G., Fulcher D., Tang M., Kemp A., et al. The -590C/T and -34C/T interleukin-4 promoter polymorphisms are not associated with atopic eczema in childhood. J Allergy Clin Immunol. 108:2001;285-287.
43. 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. 30:2000;1746-1749.
44. Dizier M.H., Sandford A., Walley A., Philippi A., Cookson W., Demenais F. Indication of linkage of serum IgE levels to the interleukin-4 gene and exclusion of the contribution of the (-590 C to T) interleukin-4 promoter polymorphism to IgE variation. Genet Epidemiol. 16:1999;84-94.
45. 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., van der Zee J.S. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun. 1:1999;61-65.
46. Howard T.D., Whittaker P.A., Zaiman A.L., Koppelman G.H., Xu J., Hanley M.T., Meyers D.A., Postma D.S., Bleecker E.R. Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol. 25:2001;377-384.
47. Heinzmann A., Mao X.Q., Akaiwa M., Kreomer R.T., Gao P.S., Ohshima K., Umeshita R., Abe Y., Braun S., Yamashita T., et al. Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet. 9:2000;549-559. This is an important study indicating that variants of IL-13 signaling are likely to be promoters of human asthma. Molecular modeling analysis suggests that the Arg110Gln polymorphism in IL13 is crucial in ligand-receptor interaction.
48. Graves P.E., Kabesch M., Halonen M., Holberg C.J., Baldini M., Fritzsch C., Weiland S.K., Erickson R.P., von Mutius E., Martinez F.D. 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. 105:2000;506-513.
49. Liu X., Nickel R., Beyer K., Wahn U., Ehrlich E., Freidhoff L.R., Bjorksten B., Beaty T.H., Huang S.K. 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. 106:2000;167-170.
50. Leung T.F., Tang N.L., Chan I.H., Li A.M., Ha G., Lam C.W. A polymorphism in the coding region of interleukin-13 gene is associated with atopy but not asthma in Chinese children. Clin Exp Allergy. 31:2001;1515-1521.
51. Celedon J.C., Soto-Quiros M.E., Palmer L.J., Senter J., Mosley J., Silverman E.K., Weiss S.T. Lack of association between a polymorphism in the interleukin-13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica. Clin Exp Allergy. 32:2002;387-390.
52. Barnes K.C. Gene-environment and gene-gene interaction studies in the molecular genetic analysis of asthma and atopy. Clin Exp Allergy. 29:(Suppl 4):1999;47-51.
53. Loots G.G., Locksley R.M., Blankespoor C.M., Wang Z.E., Miller W., Rubin E.M., Frazer K.A. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science. 288:2000;136-140. This very original paper proposes a method for identifying regulatory elements within non-coding DNA sequences, and identifies an intergenic regulatory region on chromosome 5q31.
54. Mohrs M., Blankespoor C.M., Wang Z.E., Loots G.G., Afzal V., Hadeiba H., Shinkai K., Rubin E.M., Locksley R.M. Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat Immunol. 2:2001;842-847.
55. Noguchi E., Nukaga-Nishio Y., Jian Z., Yokouchi Y., Kamioka M., Yamakawa-Kobayashi K., Hamaguchi H., Matsui A., Shibasaki M., Arinami T. 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. 62:2001;1251-1257.
56. Deichmann K., Bardutzky J., Forster J., Heinzmann A., Kuehr J. Common polymorphisms in the coding part of the IL4-receptor gene. Biochem Biophys Res Commun. 231:1997;696-697.
57. Hershey G.K., Friedrich M.F., Esswein L.A., Thomas M.L., Chatila T.A. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med. 337:1997;1720-1725.
58. 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., et al. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet. 66:2000;517-526. This first study to examine haplotypes comprised of all coding SNPs in the IL4RA gene in a large Hutterite pedigree as well as in outbred populations.
59. Wu X., Di Rienzo A., Ober C. A population genetics study of single nucleotide polymorphisms in the interleukin 4 receptor alpha (IL4RA) gene. Genes Immun. 2:2001;128-134.
60. Mitsuyasu H., Yanagihara Y., Mao X.Q., Gao P.S., Arinobu Y., Ihara K., Takabayashi A., Hara T., Enomoto T., Sasaki S., et al. Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis. J Immunol. 162:1999;1227-1231.
61. Izuhara K., Yanagihara Y., Hamasaki N., Shirakawa T., Hopkin J.M. Atopy and the human IL-4 receptor alpha chain. J Allergy Clin Immunol. 106:2000;S65-S71.
62. Oiso N., Fukai K., Ishii M. Interleukin 4 receptor alpha chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol. 142:2000;1003-1006.
63. Tanaka K., Sugiura H., Uehara M., Hashimoto Y., Donnelly C., Montgomery D.S. Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor alpha chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients. Clin Exp Allergy. 31:2001;1522-1527.
64. Haagerup A., Bjerke T., Schiotz P.O., Dahl R., Binderup H.G., Kruse T.A. No linkage and association of atopy to chromosome 16 including the interleukin-4 receptor gene. Allergy. 56:2001;775-779.
65. Wang H.Y., Shelburne C.P., Zamorano J., Kelly A.E., Ryan J.J., Keegan A.D. Cutting edge: effects of an allergy-associated mutation in the human IL- 4R alpha (Q576R) on human IL-4-induced signal transduction. J Immunol. 162:1999;4385-4389.
66. Grimbacher B., Holland S.M., Puck J.M. The interleukin-4 receptor variant Q576R in hyper-IgE syndrome. N Engl J Med. 338:1998;1073-1074.
67. Patuzzo C., Trabetti E., Malerba G., Martinati L.C., Boner A.L., Pescollderungg L., Zanoni G., Pignatti P.F. No linkage or association of the IL-4Ralpha gene Q576R mutation with atopic asthma in Italian families. J Med Genet. 37:2000;382-384.
68. Kruse S., Japha T., Tedner M., Sparholt S.H., Forster J., Kuehr J., Deichmann K.A. The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology. 96:1999;365-371.
69. Howard T.D., Koppelman G.H., Xu J., Zheng S.L., Postma D.S., Meyers D.A., Bleecker E.R. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet. 70:2002;230-236. This is an outstanding study showing the importance of gene-gene interactions in complex biological pathways.
70. Hackstein H., Hecker M., Kruse S., Bohnert A., Ober C., Deichmann K.A., Bein G. A novel polymorphism in the 5′ promoter region of the human interleukin- 4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics. 53:2001;264-269.
71. Jung T., Wagner K., Neumann C., Heusser C.H. Enhancement of human IL-4 activity by soluble IL-4 receptors in vitro. Eur J Immunol. 29:1999;864-871.
72. Borish L.C., Nelson H.S., Corren J., Bensch G., Busse W.W., Whitmore J.B., Agosti J.M. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 107:2001;963-970.
73. Ahmed S., Ihara K., Sasaki Y., Nakao F., Nishima S., Fujino T., Hara T. Novel polymorphism in the coding region of the IL-13 receptor alpha gene: association study with atopic asthma in the Japanese population. Exp Clin Immunogenet. 17:2000;18-22.
74. Shimoda K., van Deursen J., Sangster M.Y., Sarawar S.R., Carson R.T., Tripp R.A., Chu C., Quelle F.W., Nosaka T., Vignali D.A., et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 380:1996;630-633.
75. Tekkanat K.K., Maassab H.F., Cho D.S., Lai J.J., John A., Berlin A., Kaplan M.H., Lukacs N.W. IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent. J Immunol. 166:2001;3542-3548.
76. Gao P.S., Mao X.Q., Roberts M.H., Arinobu Y., Akaiwa M., Enomoto T., Dake Y., Kawai M., Sasaki S., Hamasaki N., et al. Variants of STAT6 (signal transducer and activator of transcription 6) in atopic asthma. J Med Genet. 37:2000;380-382.
77. 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. 31:2001;1509-1514.
78. Duetsch G., Illig T., Loesgen S., Rohde K., Klopp N., Herbon N., Gohlke H., Altmueller J., Wjst M. STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Hum Mol Genet. 11:2002;613-621. This is an interesting study implicating variation in the STAT6 gene in the development of eosinophilia and elevated IgE levels.
79. Collila S., Ober C., Beaty T., Bleecker E., Blumenthal M., Rich S., Cox N., the C.S.G.A. An examination of gene-environment interaction in a linkage study of asthma and household smoking. Am J Hum Genet. 69:(Suppl):2001;213.
80. Moffatt M.F., Faux J.A., Lester S., Pare P., McCluskey J.C., Spargo R., James A.L., Musk A.W., Cookson W.O.C.M. Atopy, asthma and HLA-DR genes in Australian aborigines. Am J Respir Crit Care Med. 165:(Suppl):2002;A808.
81. Van Eerdewegh P., Little R.D., Dupuis J., Del Mastro R.G., Falls K., Simon J., Torrey D., Pandit S., McKenny J., Braunschweiger K., et al. Association of the ADAM33 gene with asthma and brochial hyperresponsiveness. Nature. 418:2002;426-430. This paper reports the first asthma-susceptibility locus identified through linkage followed by positional cloning studies. It illustrates the magnitude of the task of gene discovery and the features that may be characteristic for asthma genes that are yet to be discovered.
82. Horikawa Y., Oda N., Cox N.J., Li X., Orho-Melander M., Hara M., Hinokio Y., Lindner T.H., Mashima H., Schwarz P.E., et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet. 26:2000;163-175.
83. Hakornarson H., Bjornsdottir U.S., Halapi E., Palsson S., Adalsteinsdottir E., Gislason D., Finnbogason G., Gislason T., Kristjansson K., Arnason T., et al. A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet. 71:2002;483-491.