Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene
Tóm tắt
ADAM33 has been identified as an asthma-associated gene in an out-bred population. Genetic studies suggested that the functional role of this metalloprotease was in airway remodeling. However, the mechanistic roles of the disease-associated SNPs have yet to be elucidated especially in the context of the pathophysiology of asthma. One disease-associated SNP, BC+1, which resides in intron BC toward the 5' end of ADAM33, is highly associated with the disease. The region surrounding this genetic variant was cloned into a model system to determine if there is a regulatory element within this intron that influences transcription. The BC+1 protective allele did not impose any affect on the transcription of the reporter gene. However, the at-risk allele enforced such a repressive affect on the promoter that no protein product from the reporter gene was detected. These results indicated that there exists within intron BC a regulatory element that acts as a repressor for gene expression. Moreover, since SNP BC+1 is a common genetic variant, this region may interact with other undefined regulatory elements within ADAM33 to provide a rheostat effect, which modulates pre-mRNA processing. Thus, SNP BC+1 may have an important role in the modulation of ADAM33 gene expression. These data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma.
Tài liệu tham khảo
Maniatis N, Collins A, Gibson J, Zhang W, Tapper W, Morton NE: Positional cloning by linkage disequilibrium. Am J Hum Genet. 2004, 74: 846-855. 10.1086/383589.
Morton NE, Collins A: Toward positional cloning with SNPs. Curr Opin Mol Ther. 2002, 4: 259-264.
Collins A, Lau W, De La Vega FM: Mapping genes for common diseases: the case for genetic (LD) maps. Hum Hered. 2004, 58: 2-9. 10.1159/000081451.
Blangero J: Localization and identification of human quantitative trait loci: king harvest has surely come. Curr Opin Genet Dev. 2004, 14: 233-240. 10.1016/j.gde.2004.04.009.
Rannala B: Finding genes influencing susceptibility to complex diseases in the post-genome era. Am J Pharmacogenomics. 2001, 1: 203-221. 10.2165/00129785-200101030-00005.
Botstein D, Risch N: Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet. 2003, 33 Suppl: 228-237. 10.1038/ng1090.
Varilo T, Peltonen L: Isolates and their potential use in complex gene mapping efforts. Curr Opin Genet Dev. 2004, 14: 316-323. 10.1016/j.gde.2004.04.008.
Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002, 418: 426-430. 10.1038/nature00878.
Chae SC, Yoon KH, Chung HT: Identification of novel polymorphisms in the Adam33 gene. J Hum Genet. 2003, 48: 278-281. 10.1007/s10038-003-0019-1.
Howard TD, Postma DS, Jongepier H, Moore WC, Koppelman GH, Zheng SL, Xu J, Bleecker ER, Meyers DA: Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol. 2003, 112: 717-722. 10.1016/S0091-6749(03)01939-0.
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. 10.1111/j.1365-2222.2004.01846.x.
Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, Koppelman GH, Zheng SL, Meyers DA, Bleecker ER, Postma DS: Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy. 2004, 34: 757-760. 10.1111/j.1365-2222.2004.1938.x.
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. 10.1016/j.jaci.2004.03.035.
Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, Park CS, Hong SJ, Holgate ST, Holloway JW, Shin HD: ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics. Clin Exp Allergy. 2004, 34: 860-865. 10.1111/j.1365-2222.2004.01977.x.
Cheng L, Enomoto T, Hirota T, Shimizu M, Takahashi N, Akahoshi M, Matsuda A, Dake Y, Doi S, Enomoto K, Yamasaki A, Fukuda S, Mao XQ, Hopkin JM, Tamari M, Shirakawa T: Polymorphisms in ADAM33 are associated with allergic rhinitis due to Japanese cedar pollen. Clin Exp Allergy. 2004, 34: 1192-1201. 10.1111/j.1365-2222.2004.02008.x.
Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST, Woodcock A, Ollier WE, Collins A, Custovic A, Holloway JW, John SL: Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am J Respir Crit Care Med. 2005, 172: 55-60. 10.1164/rccm.200412-1708OC.
Noguchi E, Ohtsuki Y, Tokunaga K, Yamaoka-Sageshima M, Ichikawa K, Aoki T, Shibasaki M, Arinami T: ADAM33 polymorphisms are associated with asthma susceptibility in a Japanese population. Clin Exp Allergy. 2006, 36: 602-608. 10.1111/j.1365-2222.2006.02471.x.
Kedda MA, Duffy DL, Bradley B, O'Hehir RE, Thompson PJ: ADAM33 haplotypes are associated with asthma in a large Australian population. Eur J Hum Genet. 2006, 14: 1027-1036. 10.1038/sj.ejhg.5201662.
Hirota T, Hasegawa K, Obara K, Matsuda A, Akahoshi M, Nakashima K, Shirakawa T, Doi S, Fujita K, Suzuki Y, Nakamura Y, Tamari M: Association between ADAM33 polymorphisms and adult asthma in the Japanese population. Clin Exp Allergy. 2006, 36: 884-891. 10.1111/j.1365-2222.2006.02522.x.
Gosman MM, Boezen HM, van Diemen CC, Snoeck-Stroband JB, Lapperre TS, Hiemstra PS, Ten Hacken NH, Stolk J, Postma DS: A Disintegrin and Metalloproteinase 33 and Chronic Obstructive Pulmonary Disease Pathophysiology. Thorax. 2007, 62 (3): 242-247. 10.1136/thx.2006.060988.
Orth P, Reichert P, Wang W, Prosise WW, Yarosh-Tomaine T, Hammond G, Ingram RN, Xiao L, Mirza UA, Zou J, Strickland C, Taremi SS, Le HV, Madison V: Crystal structure of the catalytic domain of human ADAM33. J Mol Biol. 2004, 335: 129-137. 10.1016/j.jmb.2003.10.037.
Woodley L, Valcarcel J: Regulation of alternative pre-mRNA splicing. Brief Funct Genomic Proteomic. 2002, 1: 266-277. 10.1093/bfgp/1.3.266.
Faustino NA, Cooper TA: Pre-mRNA splicing and human disease. Genes Dev. 2003, 17: 419-437. 10.1101/gad.1048803.
Pagani F, Baralle FE: Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet. 2004, 5: 389-396. 10.1038/nrg1327.
Schwerk C, Schulze-Osthoff K: Regulation of apoptosis by alternative pre-mRNA splicing. Mol Cell. 2005, 19: 1-13. 10.1016/j.molcel.2005.05.026.
Lewandowska MA, Stuani C, Parvizpur A, Baralle FE, Pagani F: Functional studies on the ATM intronic splicing processing element. Nucleic Acids Res. 2005, 33: 4007-4015. 10.1093/nar/gki710.
Venables JP: Unbalanced alternative splicing and its significance in cancer. Bioessays. 2006, 28: 378-386. 10.1002/bies.20390.
Kornblihtt AR: Promoter usage and alternative splicing. Curr Opin Cell Biol. 2005, 17: 262-268. 10.1016/j.ceb.2005.04.014.
Ridderstrale M, Parikh H, Groop L: Calpain 10 and type 2 diabetes: are we getting closer to an explanation?. Curr Opin Clin Nutr Metab Care. 2005, 8: 361-366.
Bureau A, Dupuis J, Falls K, Lunetta KL, Hayward B, Keith TP, Van Eerdewegh P: Identifying SNPs predictive of phenotype using random forests. Genet Epidemiol. 2005, 28: 171-182. 10.1002/gepi.20041.
Mayor C, Brudno M, Schwartz JR, Poliakov A, Rubin EM, Frazer KA, Pachter LS, Dubchak I: VISTA : visualizing global DNA sequence alignments of arbitrary length. Bioinformatics. 2000, 16: 1046-1047. 10.1093/bioinformatics/16.11.1046.
Adcock IM: Glucocorticoid-regulated transcription factors. Pulm Pharmacol Ther. 2001, 14: 211-219. 10.1006/pupt.2001.0283.
Pande V, Ramos MJ: NF-kappaB in human disease: current inhibitors and prospects for de novo structure based design of inhibitors. Curr Med Chem. 2005, 12: 357-374.
Roth M, Black JL: Transcription factors in asthma: are transcription factors a new target for asthma therapy?. Curr Drug Targets. 2006, 7: 589-595. 10.2174/138945006776818638.
Goldstrohm AC, Greenleaf AL, Garcia-Blanco MA: Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing. Gene. 2001, 277: 31-47. 10.1016/S0378-1119(01)00695-3.
Neugebauer KM: On the importance of being co-transcriptional. J Cell Sci. 2002, 115: 3865-3871. 10.1242/jcs.00073.
Neugebauer KM: Please hold--the next available exon will be right with you. Nat Struct Mol Biol. 2006, 13: 385-386. 10.1038/nsmb0506-385.
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 post-transcriptional regulation. Am J Respir Cell Mol Biol. 2003, 29: 571-582. 10.1165/rcmb.2003-0028OC.
Powell RM, Wicks J, Holloway JW, Holgate ST, Davies DE: The splicing and fate of ADAM33 transcripts in primary human airways fibroblasts. Am J Respir Cell Mol Biol. 2004, 31: 13-21. 10.1165/rcmb.2003-0330OC.
Haitchi HM, Powell RM, Shaw TJ, Howarth PH, Wilson SJ, Wilson DI, Holgate ST, Davies DE: ADAM33 expression in asthmatic airways and human embryonic lungs. Am J Respir Crit Care Med. 2005, 171: 958-965. 10.1164/rccm.200409-1251OC.
Seals DF, Courtneidge SA: The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 2003, 17: 7-30. 10.1101/gad.1039703.
Garlisi CG, Zou J, Devito KE, Tian F, Zhu FX, Liu J, Shah H, Wan Y, Motasim Billah M, Egan RW, Umland SP: Human ADAM33: protein maturation and localization. Biochem Biophys Res Commun. 2003, 301: 35-43. 10.1016/S0006-291X(02)02976-5.
Hirota T, Suzuki Y, Hasegawa K, Obara K, Matsuda A, Akahoshi M, Nakashima K, Cheng L, Takahashi N, Shimizu M, Doi S, Fujita K, Enomoto T, Ebisawa M, Yoshihara S, Nakamura Y, Kishi F, Shirakawa T, Tamari M: Functional haplotypes of IL-12B are associated with childhood atopic asthma. J Allergy Clin Immunol. 2005, 116: 789-795. 10.1016/j.jaci.2005.06.010.
Faffe DS, Flynt L, Bourgeois K, Panettieri RA, Shore SA: Interleukin-13 and interleukin-4 induce vascular endothelial growth factor release from airway smooth muscle cells: role of vascular endothelial growth factor genotype. Am J Respir Cell Mol Biol. 2006, 34: 213-218. 10.1165/rcmb.2005-0147OC.
Tergaonkar V: NFkappaB pathway: a good signaling paradigm and therapeutic target. Int J Biochem Cell Biol. 2006, 38: 1647-1653. 10.1016/j.biocel.2006.03.023.
Barnes PJ: Transcription factors in airway diseases. Lab Invest. 2006, 86: 867-872. 10.1038/labinvest.3700456.
Zuker M: Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003, 31: 3406-3415. 10.1093/nar/gkg595.
Di Paola R, Frittitta L, Miscio G, Bozzali M, Baratta R, Centra M, Spampinato D, Santagati MG, Ercolino T, Cisternino C, Soccio T, Mastroianno S, Tassi V, Almgren P, Pizzuti A, Vigneri R, Trischitta V: A variation in 3' UTR of hPTP1B increases specific gene expression and associates with insulin resistance. Am J Hum Genet. 2002, 70: 806-812. 10.1086/339270.
Capon F, Allen MH, Ameen M, Burden AD, Tillman D, Barker JN, Trembath RC: A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet. 2004, 13: 2361-2368. 10.1093/hmg/ddh273.
Wang H, Zhang Z, Chu W, Hale T, Cooper JJ, Elbein SC: Molecular screening and association analyses of the interleukin 6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity. J Clin Endocrinol Metab. 2005, 90: 1123-1129. 10.1210/jc.2004-1606.
Ladd AN, Stenberg MG, Swanson MS, Cooper TA: Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev Dyn. 2005, 233: 783-793. 10.1002/dvdy.20382.
Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W: Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem. 2005, 280: 32618-32624. 10.1074/jbc.M504942200.
Thomas KH, Meyn P, Suttorp N: Single nucleotide polymorphism in 5'-flanking region reduces transcription of surfactant protein B gene in H441 cells. Am J Physiol Lung Cell Mol Physiol. 2006, 291: L386-90. 10.1152/ajplung.00193.2005.
Cooper TA: Use of minigene systems to dissect alternative splicing elements. Methods. 2005, 37: 331-340. 10.1016/j.ymeth.2005.07.015.
dbSNP Home Page. [http://www.ncbi.nlm.nih.gov/projects/SNP/]
Human (Homo Sapiens) Genome Browser Gateway. [http://genome.ucsc.edu/cgi-bin/hgGateway]
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