Exome Sequencing of Phenotypic Extremes Identifies and as Interacting Modifiers of Chronic Infection in Cystic Fibrosis

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Whole exome and whole genome sequencing provide the opportunity to test for associations between expressed traits and genetic variants that cannot be tested with chip technology, particularly variants that are too rare to be included on chips designed for genome-wide association analysis. We used exome sequencing to identify variants in CAV2 and TMC6 that modify the age-of-onset of chronic Pseudomonas aeruginosa infection among children with cystic fibrosis, and validated our findings in a large cohort of children with cystic fibrosis. For a fixed number of study participants, it is known that the extreme phenotypes design provides greater statistical power than a random sampling design. In the extreme phenotypes design, one compares the frequency of a given set of genetic variants in one extreme of age-of-onset (early onset) to that in the other extreme (late onset). Here, we employed an alternative design that compares genetic frequencies in exomes sampled from one extreme to that among exomes from a large set of controls. We show that this design confers substantially greater statistical power for discovery of CAV2 and TMC6 and provide general conditions under which this single extreme versus control design is more powerful than the extreme phenotypes design.

Vyšlo v časopise: Exome Sequencing of Phenotypic Extremes Identifies and as Interacting Modifiers of Chronic Infection in Cystic Fibrosis. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005273
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005273

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1. Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, et al. (2010) Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 363 : 1991–2003. doi: 10.1056/NEJMoa0909825 21083385

2. Chmiel JF, Konstan MW (2007) Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med 28 : 331–346. 17467552

3. Gibson RL, Burns JL, Ramsey BW (2003) Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 168 : 918–951. 14555458

4. Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM (2003) Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2 : 29–34. 15463843

5. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL (2002) Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 34 : 91–100. 12112774

6. Proesmans M, Balinska-Miskiewicz W, Dupont L, Bossuyt X, Verhaegen J, et al. (2006) Evaluating the "Leeds criteria" for Pseudomonas aeruginosa infection in a cystic fibrosis centre. Eur Respir J 27 : 937–943. 16707392

7. Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, et al. (2005) Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA 293 : 581–588. 15687313

8. Demko CA, Byard PJ, Davis PB (1995) Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 48 : 1041–1049. 7775991

9. Henry RL, Mellis CM, Petrovic L (1992) Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 12 : 158–161. 1641272

10. Doring G, Taccetti G, Campana S, Festini F, Mascherini M (2006) Eradication of Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J 27 : 653. 16507869

11. Zemanick ET, Accurso FJ (2014) Cystic fibrosis transmembrane conductance regulator and pseudomonas. Am J Respir Crit Care Med 189 : 763–765. doi: 10.1164/rccm.201402-0209ED 24684355

12. Green DM, Collaco JM, McDougal KE, Naughton KM, Blackman SM, et al. (2012) Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis. J Pediatr 161 : 290–295 e291. doi: 10.1016/j.jpeds.2012.01.042 22364820

13. Dorfman R, Sandford A, Taylor C, Huang B, Frangolias D, et al. (2008) Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 118 : 1040–1049. doi: 10.1172/JCI33754 18292811

14. Dorfman R, Taylor C, Lin F, Sun L, Sandford A, et al. (2011) Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis. Pediatr Pulmonol 46 : 385–392. doi: 10.1002/ppul.21372 20967843

15. Haerynck F, Van Steen K, Cattaert T, Loeys B, Van Daele S, et al. (2012) Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients. Hum Immunol 73 : 1175–1183. doi: 10.1016/j.humimm.2012.08.010 22940091

16. Emond MJ, Louie T, Emerson J, Zhao W, Mathias RA, et al. (2012) Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nat Genet 44 : 886–889. doi: 10.1038/ng.2344 22772370

17. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, et al. (2005) Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 353 : 1443–1453. 16207846

18. Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, et al. (2011) Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet 43 : 539–546. doi: 10.1038/ng.838 21602797

19. Treggiari MM, Rosenfeld M, Mayer-Hamblett N, Retsch-Bogart G, Gibson RL, et al. (2009) Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'. Contemp Clin Trials 30 : 256–268. doi: 10.1016/j.cct.2009.01.003 19470318

20. Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, et al. (2012) Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet 91 : 224–237. doi: 10.1016/j.ajhg.2012.06.007 22863193

21. McKone EF, Goss CH, Aitken ML (2006) CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest 130 : 1441–1447. 17099022

22. Lawless JF (2003) Statistical Models and Methods for Lifetime Data. Hoboken, New Jersey and Canada: John Wiley & Sons.

23. Zaas DW, Swan ZD, Brown BJ, Li G, Randell SH, et al. (2009) Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa. J Biol Chem 284 : 9955–9964. doi: 10.1074/jbc.M808629200 19211560

24. Zaas DW, Swan Z, Brown BJ, Wright JR, Abraham SN (2009) The expanding roles of caveolin proteins in microbial pathogenesis. Commun Integr Biol 2 : 535–537. 20195460

25. Wright JM, Joseloff E, Nikolsky Y, Serebriyskaya T, Wetmore D (2010) Interactions between an inflammatory response to infection and protein trafficking pathways favor correction of defective protein trafficking in Cystic Fibrosis. Bioinformation 5 : 228–233. 21364822

26. Bajmoczi M, Gadjeva M, Alper SL, Pier GB, Golan DE (2009) Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa. Am J Physiol Cell Physiol 297: C263–277. doi: 10.1152/ajpcell.00527.2008 19386787

27. Zaas DW, Duncan MJ, Li G, Wright JR, Abraham SN (2005) Pseudomonas invasion of type I pneumocytes is dependent on the expression and phosphorylation of caveolin-2. J Biol Chem 280 : 4864–4872. 15545264

28. Wright JM, Nikolsky Y, Serebryiskaya T, Wetmore DR (2009) MetaMiner (CF): a disease-oriented bioinformatics analysis environment. Methods Mol Biol 563 : 353–367. doi: 10.1007/978-1-60761-175-2_18 19597794

29. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, et al. (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46 : 310–315. doi: 10.1038/ng.2892 24487276

30. Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, et al. (2000) Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407 : 762–764. 11048725

31. Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, et al. (2001) Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 183 : 444–452. 11133376

32. Carlsson M, Eriksson L, Pressler T, Kornfalt R, Mared L, et al. (2007) Autoantibody response to BPI predict disease severity and outcome in cystic fibrosis. J Cyst Fibros 6 : 228–233. 17166780

33. Trzcinska-Daneluti AM, Ly D, Huynh L, Jiang C, Fladd C, et al. (2009) High-content functional screen to identify proteins that correct F508del-CFTR function. Mol Cell Proteomics 8 : 780–790. doi: 10.1074/mcp.M800268-MCP200 19088066

34. Lazarczyk M, Dalard C, Hayder M, Dupre L, Pignolet B, et al. (2012) EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation. PLoS One 7: e39995. doi: 10.1371/journal.pone.0039995 22761942

35. Lazarczyk M, Favre M (2008) Role of Zn2+ ions in host-virus interactions. J Virol 82 : 11486–11494. doi: 10.1128/JVI.01314-08 18787005

36. Bezzerri V, d'Adamo P, Rimessi A, Lanzara C, Crovella S, et al. (2011) Phospholipase C-beta3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells. Journal of immunology 186 : 4946–4958. doi: 10.4049/jimmunol.1003535 21411730

37. Harder J, Meyer-Hoffert U, Teran LM, Schwichtenberg L, Bartels J, et al. (2000) Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. American journal of respiratory cell and molecular biology 22 : 714–721. 10837369

38. Smith JL, Campos SK, Ozbun MA (2007) Human papillomavirus type 31 uses a caveolin 1 -⁠ and dynamin 2-mediated entry pathway for infection of human keratinocytes. J Virol 81 : 9922–9931. 17626097

39. Day PM, Lowy DR, Schiller JT (2003) Papillomaviruses infect cells via a clathrin-dependent pathway. Virology 307 : 1–11. 12667809

40. Derkach A, Chiang T, Gong J, Addis L, Dobbins S, et al. (2014) Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic. Bioinformatics 30 : 2179–2188. doi: 10.1093/bioinformatics/btu196 24733292

41. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, et al. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25 : 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

42. Rosenfeld M, Emerson J, McNamara S, Thompson V, Ramsey BW, et al. (2012) Risk factors for age at initial Pseudomonas acquisition in the cystic fibrosis epic observational cohort. J Cyst Fibros 11 : 446–453. doi: 10.1016/j.jcf.2012.04.003 22554417

43. Fleming TR, Harrington, David P (2005) Conting Processes and Survival Analysis. Hoboken, New Jersey: John Wiley and Sons.