1932

Abstract

In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype–phenotype relationships. The non- genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies.

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2018-08-31
2024-06-16
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Literature Cited

  1. 1.  Accurso FJ, Sontag MK 2008. Gene modifiers in cystic fibrosis. J. Clin. Investig. 118:839–41
    [Google Scholar]
  2. 2.  Ahn W, Kim KH, Lee JA, Kim JY, Choi JY et al. 2001. Regulatory interaction between the cystic fibrosis transmembrane conductance regulator and HCO3 salvage mechanisms in model systems and the mouse pancreatic duct. J. Biol. Chem. 276:17236–43
    [Google Scholar]
  3. 3.  Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D 1999. HLA class II polymorphism in cystic fibrosis: a possible modifier of pulmonary phenotype. Am. J. Respir. Crit. Care Med. 159:1464–68
    [Google Scholar]
  4. 4.  Atalar M, Vecchio-Pagan B, Strug LJ, Pace RG, Corvol H et al. 2017. Diabetes in cystic fibrosis and type 2 diabetes (T2D) have overlapping genetic risk architecture Poster presented at Am. Soc. Hum. Genet. Meet Orlando, FL: Oct 17–21
    [Google Scholar]
  5. 5.  Augarten A, Ben Tov A, Madgar I, Barak A, Akons H et al. 2008. The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype. Eur. J. Gastroenterol. Hepatol. 20:164–68
    [Google Scholar]
  6. 6.  Bagorda A, Guerra L, Di Sole F, Hemle-Kolb C, Cardone RA et al. 2002. Reciprocal protein kinase A regulatory interactions between cystic fibrosis transmembrane conductance regulator and Na+/H+ exchanger isoform 3 in a renal polarized epithelial cell model. J. Biol. Chem. 277:21480–88
    [Google Scholar]
  7. 7.  Barrios CR, Ortega VE, Ampleford EJ, Busse WW, Castro M et al. 2017. Rare, pathogenic CFTR variants are associated with lung function in a multi-ethnic population from the Severe Asthma Research Program (SARP). Am. J. Respir. Crit. Care Med. 195:A3245
    [Google Scholar]
  8. 8.  Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC et al. 2009. Genetic modifiers of liver disease in cystic fibrosis. JAMA 302:1076–83
    [Google Scholar]
  9. 9.  Birket SE, Davis JM, Fernandez CM, Tuggle KL, Oden AM et al. 2018. Development of an airway mucus defect in the cystic fibrosis rat. JCI Insight 3:e97199
    [Google Scholar]
  10. 10.  Blackman SM, Commander CW, Watson C, Arcara KM, Strug LJ et al. 2013. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes 62:3627–35
    [Google Scholar]
  11. 11.  Blackman SM, Deering-Brose R, McWilliams R, Naughton K, Coleman B et al. 2006. Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Gastroenterology 131:1030–39
    [Google Scholar]
  12. 12.  Blackman SM, Hsu S, Ritter SE, Naughton KM, Wright FA et al. 2009. A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis. Diabetologia 52:1858–65
    [Google Scholar]
  13. 13.  Blackman SM, Hsu S, Vanscoy LL, Collaco JM, Ritter SE et al. 2009. Genetic modifiers play a substantial role in diabetes complicating cystic fibrosis. J. Clin. Endocrinol. Metab. 94:1302–9
    [Google Scholar]
  14. 14.  Boelle PY, Viviani L, Busson PF, Olesen HV, Ravilly S et al. 2012. Reference percentiles for FEV1 and BMI in European children and adults with cystic fibrosis. Orphanet J. Rare Dis. 7:64
    [Google Scholar]
  15. 15.  Bombieri C, Claustres M, De Boeck K, Derichs N, Dodge J et al. 2011. Recommendations for the classification of diseases as CFTR-related disorders. J. Cyst. Fibros. 10:Suppl. 2S86–102
    [Google Scholar]
  16. 16.  Bombieri C, Seia M, Castellani C 2015. Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders. Semin. Respir. Crit. Care Med. 36:180–93
    [Google Scholar]
  17. 17.  Bradford EM, Sartor MA, Gawenis LR, Clarke LL, Shull GE 2009. Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296:G886–98
    [Google Scholar]
  18. 18.  Bradley GM, Blackman SM, Watson CP, Doshi VK, Cutting GR 2012. Genetic modifiers of nutritional status in cystic fibrosis. Am. J. Clin. Nutr. 96:1299–308
    [Google Scholar]
  19. 19.  Bremer LA, Blackman SM, Vanscoy LL, McDougal KE, Bowers A et al. 2008. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Hum. Mol. Genet. 17:2228–37
    [Google Scholar]
  20. 20.  Brennan ML, Schrijver I 2016. Cystic fibrosis: a review of associated phenotypes, use of molecular diagnostic approaches, genetic characteristics, progress, and dilemmas. J. Mol. Diagn. 18:3–14
    [Google Scholar]
  21. 21. Broad Inst. MIT Harv. 2017. GTEx Portal V7, updated Sept. 18. https://www.gtexportal.org
    [Google Scholar]
  22. 22.  Büscher R, Grasemann H 2006. Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?. Naunyn Schmiedeberg's Arch. Pharmacol. 374:65–77
    [Google Scholar]
  23. 23.  Button B, Cai LH, Ehre C, Kesimer M, Hill DB et al. 2012. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337:937–41
    [Google Scholar]
  24. 24.  Castellani C 2013. CFTR2: How will it help care?. Paediatr. Respir. Rev. 14:Suppl. 12–5
    [Google Scholar]
  25. 25.  Chalmers JD, Fleming GB, Hill AT, Kilpatrick DC 2011. Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: a review and meta-analysis. Glycobiology 21:271–82
    [Google Scholar]
  26. 26. Child. Hosp. Pa. 2014. 4DGenome https://4dgenome.research.chop.edu
    [Google Scholar]
  27. 27.  Cohn JA 2005. Reduced CFTR function and the pathobiology of idiopathic pancreatitis. J. Clin. Gastroenterol. 39:S70–77
    [Google Scholar]
  28. 28.  Collaco JM, Blackman SM, Raraigh KS, Corvol H, Rommens JM et al. 2016. Sources of variation in sweat chloride measurements in cystic fibrosis. Am. J. Respir. Crit. Care Med. 194:1375–82
    [Google Scholar]
  29. 29.  Collaco JM, Cutting GR 2008. Update on gene modifiers in cystic fibrosis. Curr. Opin. Pulm. Med. 14:559–66
    [Google Scholar]
  30. 30.  Corey M, Edwards L, Levison H, Knowles M 1997. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J. Pediatr. 131:809–14
    [Google Scholar]
  31. 31.  Corvol H, Blackman SM, Boelle PY, Gallins PJ, Pace RG et al. 2015. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat. Commun. 6:8382
    [Google Scholar]
  32. 32.  Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM et al. 2006. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999–2002. Diabetes Care 29:1263–68
    [Google Scholar]
  33. 33.  Cutting GR 2005. Modifier genetics: cystic fibrosis. Annu. Rev. Genom. Hum. Genet. 6:237–60
    [Google Scholar]
  34. 34.  Cutting GR 2010. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann. N.Y. Acad. Sci. 1214:57–69
    [Google Scholar]
  35. 35.  Cutting GR 2015. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat. Rev. Genet. 16:45–56
    [Google Scholar]
  36. 36. Cyst. Fibros. Cent. 2011. Cystic Fibrosis Mutation Database Updated Apr. 25. http://www.genet.sickkids.on.ca/cftr
    [Google Scholar]
  37. 37. Cyst. Fibros. Found., Johns Hopkins Univ. Hosp. Sick Child. 2017. CFTR2 variant list history Updated Mar. 17. https://cftr2.org/mutations_history
    [Google Scholar]
  38. 38. Cyst. Fibros. Genotype-Phenotype Consort. 1993. Correlation between genotype and phenotype in patients with cystic fibrosis. N. Engl. J. Med. 329:1308–13
    [Google Scholar]
  39. 39.  Dahl M, Tybjaerg-Hansen A, Lange P, Nordestgaard BG 1998. ΔF508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 351:1911–13
    [Google Scholar]
  40. 40.  Dang H, Gallins PJ, Pace RG, Guo XL, Stonebraker JR et al. 2016. Novel variation at chr11p13 associated with cystic fibrosis lung disease severity. Hum. Genome Var. 3:16020
    [Google Scholar]
  41. 41.  Davis PB 2006. Cystic fibrosis since 1938. Am. J. Respir. Crit. Care Med. 173:475–82
    [Google Scholar]
  42. 42.  de Gracia J, Mata F, Alvarez A, Casals T, Gatner S et al. 2005. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax 60:558–63
    [Google Scholar]
  43. 43.  De Lisle RC, Borowitz D 2013. The cystic fibrosis intestine. Cold Spring Harb. Perspect. Med. 3:a009753
    [Google Scholar]
  44. 44.  di Sant'Agnese PE, Andersen DH 1948. Cystic fibrosis of the pancreas. Prog. Pediatr. Study 1:160–76
    [Google Scholar]
  45. 45.  Doershuk CF 2001. Cystic Fibrosis in the 20th Century: People, Events, and Progress Cleveland, OH: AM Publ.
    [Google Scholar]
  46. 46.  Dorfman R 2012. Modifier gene studies to identify new therapeutic targets in cystic fibrosis. Curr. Pharm. Des. 18:674–82
    [Google Scholar]
  47. 47.  Dorfman R, Li W, Sun L, Lin F, Wang Y et al. 2009. Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results. Hum. Genet. 126:763–78
    [Google Scholar]
  48. 48.  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. Investig. 118:1040–49
    [Google Scholar]
  49. 49.  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. 46:385–92
    [Google Scholar]
  50. 50.  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. 353:1443–53
    [Google Scholar]
  51. 51.  Dupuis A, Keenan K, Ooi CY, Dorfman R, Sontag MK et al. 2016. Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Genet. Med. 18:333–40
    [Google Scholar]
  52. 52.  Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, Durie P 2002. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 123:1857–64
    [Google Scholar]
  53. 53.  Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP et al. 2006. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N. Engl. J. Med. 354:229–40
    [Google Scholar]
  54. 54.  Emond MJ, Louie T, Emerson J, Chong JX, Mathias RA et al. 2015. Exome sequencing of phenotypic extremes identifies CAV2 and TMC6 as interacting modifiers of chronic Pseudomonas aeruginosa infection in cystic fibrosis. PLOS Genet 11:e1005273
    [Google Scholar]
  55. 55.  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. 44:886–89
    [Google Scholar]
  56. 56.  Esther CR, O'Neal W, Polineni D, Mahon A, Isaacman S, Knowles M 2017. A combined ’omics strategy identifies the methionine salvage pathway as a novel therapeutic target for cystic fibrosis airways disease. Am. J. Respir. Crit. Care Med. 195:A4852
    [Google Scholar]
  57. 57.  Esther CR, Polineni D, Mahon A, Isaacman S, Bonfield TL et al. 2017. A novel therapeutic targeting the methionine salvage pathway reduces airway inflammation. Pediatr. Pulmonol. 52:S328–29
    [Google Scholar]
  58. 58.  Fossum SL, Mutolo MJ, Tugores A, Ghosh S, Randell SH et al. 2017. Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease. J. Biol. Chem. 292:10938–49
    [Google Scholar]
  59. 59.  Fossum SL, Mutolo MJ, Yang R, Dang H, O'Neal WK et al. 2014. Ets homologous factor regulates pathways controlling response to injury in airway epithelial cells. Nucleic Acids Res 42:13588–98
    [Google Scholar]
  60. 60.  Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML et al. (Pulmozyme Study Group). 1994. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N. Engl. J. Med. 331:637–42
    [Google Scholar]
  61. 61.  Furlan LL, Marson FA, Ribeiro JD, Bertuzzo CS, Salomao Junior JB, Souza DR 2016. IL8 gene as modifier of cystic fibrosis: unraveling the factors which influence clinical variability. Hum. Genet. 135:881–94
    [Google Scholar]
  62. 62.  Gallati S 2014. Disease-modifying genes and monogenic disorders: experience in cystic fibrosis. Appl. Clin. Genet. 7:133–46
    [Google Scholar]
  63. 63.  Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K et al. 2015. A gene-based association method for mapping traits using reference transcriptome data. Nat. Genet. 47:1091–98
    [Google Scholar]
  64. 64.  Gaskin KJ, Durie PR, Lee L, Hill R, Forstner GG 1984. Colipase and lipase secretion in childhood-onset pancreatic insufficiency. Delineation of patients with steatorrhea secondary to relative colipase deficiency. Gastroenterology 86:1–7
    [Google Scholar]
  65. 65.  Geborek A, Hjelte L 2011. Association between genotype and pulmonary phenotype in cystic fibrosis patients with severe mutations. J. Cyst. Fibros. 10:187–92
    [Google Scholar]
  66. 66.  Gong J, Zhang L, Baskurt Z, Panjwani N, Xiao B et al. 2018. A novel integration statistic suggests gene expression in the exocrine pancreas may contribute to intestinal obstruction in cystic fibrosis. Pediatr. Pulmonol. In press
    [Google Scholar]
  67. 67.  Goss CH, Newsom SA, Schildcrout JS, Sheppard L, Kaufman JD 2004. Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis. Am. J. Respir. Crit. Care Med. 169:816–21
    [Google Scholar]
  68. 68.  Green DM, Collaco JM, McDougal KE, Naughton KM, Blackman SM, Cutting GR 2012. Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis. J. Pediatr. 161:290–95
    [Google Scholar]
  69. 69.  Guillot L, Beucher J, Tabary O, Le Rouzic P, Clement A, Corvol H 2014. Lung disease modifier genes in cystic fibrosis. Int. J. Biochem. Cell Biol. 52:83–93
    [Google Scholar]
  70. 70.  Guimbellot J, Sharma J, Rowe SM 2017. Toward inclusive therapy with CFTR modulators: progress and challenges. Pediatr. Pulmonol. 52:S4–14
    [Google Scholar]
  71. 71.  Gusev A, Ko A, Shi H, Bhatia G, Chung W et al. 2016. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48:245–52
    [Google Scholar]
  72. 72.  Habara A, Steinberg MH 2016. Minireview: genetic basis of heterogeneity and severity in sickle cell disease. Exp. Biol. Med. 241:689–96
    [Google Scholar]
  73. 73.  Hanrahan JW, Matthes E, Carlile G, Thomas DY 2017. Corrector combination therapies for F508del-CFTR. Curr. Opin. Pharmacol. 34:105–11
    [Google Scholar]
  74. 74.  Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG et al. 2012. Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. PLOS Genet 8:e1002580
    [Google Scholar]
  75. 75.  Hillian AD, Londono D, Dunn JM, Goddard KA, Pace RG et al. 2008. Modulation of cystic fibrosis lung disease by variants in interleukin-8. Genes Immun 9:501–8
    [Google Scholar]
  76. 76.  Horton R, Wilming L, Rand V, Lovering RC, Bruford EA et al. 2004. Gene map of the extended human MHC. Nat. Rev. Genet. 5:889–99
    [Google Scholar]
  77. 77.  Karnes JH, Bastarache L, Shaffer CM, Gaudieri S, Xu Y et al. 2017. Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci. Transl. Med. 9:eaai8708
    [Google Scholar]
  78. 78.  Kerem B, Kerem E 1995. The molecular basis for disease variability in cystic fibrosis. Eur. J. Hum. Genet. 4:65–73
    [Google Scholar]
  79. 79.  Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK et al. 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–80
    [Google Scholar]
  80. 80.  Kerem E, Corey M, Kerem B-S, Rommens J, Markiewicz D et al. 1990. The relation between genotype and phenotype in cystic fibrosis—analysis of the most common mutation (ΔF508). N. Engl. J. Med. 323:1517–22
    [Google Scholar]
  81. 81.  Kesimer M, Ehre C, Burns KA, Davis CW, Sheehan JK, Pickles RJ 2013. Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways. Mucosal Immunol 6:379–92
    [Google Scholar]
  82. 82.  Knowles MR 2006. Gene modifiers of lung disease. Curr. Opin. Pulm. Med. 12:416–21
    [Google Scholar]
  83. 83.  Knowles MR, Boucher RC 2002. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Investig. 109:571–77
    [Google Scholar]
  84. 84.  Knowles MR, Drumm M 2012. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb. Perspect. Med. 2:a009548
    [Google Scholar]
  85. 85.  Knowlton RG, Cohen-Haguenauer O, Van Cong N, Frezal J, Brown VA et al. 1985. A polymorphic DNA marker linked to cystic fibrosis is located on chromosome 7. Nature 318:380–82
    [Google Scholar]
  86. 86.  Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D et al. 2012. Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. PNAS 109:E2343–52
    [Google Scholar]
  87. 87.  Koch C, Cuppens H, Rainisio M, Madessani U, Harms H et al. 2001. European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations. Pediatr. Pulmonol. 31:1–12
    [Google Scholar]
  88. 88.  Konigshoff M, Wilhelm A, Jahn A, Sedding D, Amarie OV et al. 2007. The angiotensin II receptor 2 is expressed and mediates angiotensin II signaling in lung fibrosis. Am. J. Respir. Cell Mol. Biol. 37:640–50
    [Google Scholar]
  89. 89.  Kopp BT, Ortega-García JA, Sadreameli SC, Wellmerling J, Cormet-Boyaka E et al. 2016. The impact of secondhand smoke exposure on children with cystic fibrosis: a review. Int. J. Environ. Res. Public Health 13:1003
    [Google Scholar]
  90. 90.  Kormann MSD, Dewerth A, Eichner F, Baskaran P, Hector A et al. 2017. Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity. PLOS ONE 12:e0183526
    [Google Scholar]
  91. 91.  Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J et al. 1992. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am. J. Hum. Genet. 50:1178
    [Google Scholar]
  92. 92.  Ledder O, Haller W, Couper RT, Lewindon P, Oliver M 2014. Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations. J. Gastroenterol. Hepatol. 29:1954–62
    [Google Scholar]
  93. 93.  Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D et al. 2015. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am. J. Respir. Crit. Care Med. 191:194–200
    [Google Scholar]
  94. 94.  Li J, Zhao X, Li X, Lerea KM, Olson SC 2007. Angiotensin II type 2 receptor-dependent increases in nitric oxide synthase expression in the pulmonary endothelium is mediated via a Gαi3/Ras/Raf/MAPK pathway. Am. J. Physiol. Cell Physiol. 292:C2185–96
    [Google Scholar]
  95. 95.  Li W, Soave D, Miller MR, Keenan K, Lin F et al. 2014. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. Hum. Genet. 133:151–61
    [Google Scholar]
  96. 96.  Mackie A, Thornton S, Edenborough F 2003. Cystic fibrosis-related diabetes. Diabet. Med. 20:425–36
    [Google Scholar]
  97. 97.  Massie J, Robinson PJ, Cooper PJ 2016. The story of cystic fibrosis 1965–2015. J. Paediatr. Child. Health 52:991–94
    [Google Scholar]
  98. 98.  McKone EF, Emerson SS, Edwards KL, Aitken ML 2003. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 361:1671–76
    [Google Scholar]
  99. 99.  Mekus F, Ballmann M, Bronsveld I, Bijman J, Veeze H, Tümmler B 2000. Categories of ΔF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res 3:277–93
    [Google Scholar]
  100. 100.  Moheet A, Moran A 2017. CF-related diabetes: containing the metabolic miscreant of cystic fibrosis. Pediatr. Pulmonol. 52:S37–43
    [Google Scholar]
  101. 101.  Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS et al. 2010. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care 33:2677–83
    [Google Scholar]
  102. 102.  Moran A, Hardin D, Rodman D, Allen HF, Beall RJ et al. 1999. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus. Diabetes Res. Clin. Pract. 45:61–73
    [Google Scholar]
  103. 103.  Mornet E, Simon-Bouy B, Serre JL, Estivill X, Farrall M et al. 1988. Genetic differences between cystic fibrosis with and without meconium ileus. Lancet 331:376–78
    [Google Scholar]
  104. 104.  Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV et al. 2012. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44:981–90
    [Google Scholar]
  105. 105.  Nielsen AO, Qayum S, Bouchelouche PN, Laursen LC, Dahl R, Dahl M 2016. Risk of asthma in heterozygous carriers for cystic fibrosis: a meta-analysis. J. Cyst. Fibros. 15:563–67
    [Google Scholar]
  106. 106.  Noone PG, Knowles MR 2001. ‘CFTR-opathies’: disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respir. Res. 2:328–32
    [Google Scholar]
  107. 107.  Oates GR, Schechter MS 2016. Socioeconomic status and health outcomes: cystic fibrosis as a model. Expert Rev. Respir. Med. 10:967–77
    [Google Scholar]
  108. 108.  O'Neal WK, Gallins P, Pace RG, Dang H, Wolf WE et al. 2015. Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes. Am. J. Hum. Genet. 96:318–28
    [Google Scholar]
  109. 109.  Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C et al. 2011. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 140:153–61
    [Google Scholar]
  110. 110. Penn State Coll. Med. 2017. 3D Genome Browser http://promoter.bx.psu.edu/hi-c
    [Google Scholar]
  111. 111.  Polineni D, Dang H, Gallins PJ, Jones LC, Pace RG et al. 2018. Airway mucosal host defense is key to genomic regulation of cystic fibrosis lung disease severity. Am. J. Respir. Crit. Care Med. 197:79–93
    [Google Scholar]
  112. 112.  Qiao D, Lange C, Beaty TH, Crapo JD, Barnes KC et al. 2016. Exome sequencing analysis in severe, early-onset chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 193:1353–63
    [Google Scholar]
  113. 113.  Quinton PM 1999. Physiological basis of cystic fibrosis: a historical perspective. Physiol. Rev. 79:S3–22
    [Google Scholar]
  114. 114.  Ramsay KA, Stockwell RE, Bell SC, Kidd TJ 2016. Infection in cystic fibrosis: impact of the environment and climate. Expert Rev. Respir. Med. 10:505–19
    [Google Scholar]
  115. 115.  Ratjen F, Bell SC, Rowe SM, Goss CH, Quittner AL, Bush A 2015. Cystic fibrosis. Nat. Rev. Dis. Primers 1:15010
    [Google Scholar]
  116. 116. RIKEN. 2017. FANTOM: Functional Annotation of the Mammalian Genome http://fantom.gsc.riken.jp
    [Google Scholar]
  117. 117.  Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R et al. 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–73
    [Google Scholar]
  118. 118.  Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G et al. 1989. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245:1059–65
    [Google Scholar]
  119. 119.  Rosen BH, Chanson M, Gawenis LR, Liu J, Sofoluwe A et al. 2018. Animal and model systems for studying cystic fibrosis. J. Cyst. Fibros. 17:S28–34
    [Google Scholar]
  120. 120.  Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J et al. 2017. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N. Engl. J. Med. 377:2024–35
    [Google Scholar]
  121. 121.  Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M et al. 1996. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat. Genet. 12:280–87
    [Google Scholar]
  122. 122.  Rymut SM, Harker A, Corey DA, Burgess JD, Sun H et al. 2013. Reduced microtubule acetylation in cystic fibrosis epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 305:L419–31
    [Google Scholar]
  123. 123.  Sathe MN, Freeman AJ 2016. Gastrointestinal, pancreatic, and hepatobiliary manifestations of cystic fibrosis. Pediatr. Clin. N. Am. 63:679–98
    [Google Scholar]
  124. 124.  Schechter MS 2011. Nongenetic influences on cystic fibrosis outcomes. Curr. Opin. Pulm. Med. 17:448–54
    [Google Scholar]
  125. 125.  Snell G, Reed A, Stern M, Hadjiliadis D 2017. The evolution of lung transplantation for cystic fibrosis: a 2017 update. J. Cyst. Fibros. 16:553–64
    [Google Scholar]
  126. 126.  Sontag MK, Corey M, Hokanson JE, Marshall JA, Sommer SS et al. 2006. Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening. J. Pediatr. 149:650–57
    [Google Scholar]
  127. 127.  Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM et al. 2017. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J. Pediatr. 181S:S27–32
    [Google Scholar]
  128. 128.  Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H et al. 2013. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat. Genet. 45:1160–67
    [Google Scholar]
  129. 129.  Stolzenburg LR, Yang R, Kerschner JL, Fossum S, Xu M et al. 2017. Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity. Nucleic Acids Res 45:8773–84
    [Google Scholar]
  130. 130.  Stonebraker JR, Dang H, Pace RG, Boyles S, Quinney N et al. 2017. Exploring the biologic basis of the chr11p13 CF lung disease modifying locus using CF airway epithelial cells. Pediatr. Pulmonol. 52:S265
    [Google Scholar]
  131. 131.  Strug LJ, Gonska T, He G, Keenan K, Ip W et al. 2016. Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics. Hum. Mol. Genet. 25:4590–600
    [Google Scholar]
  132. 132.  Sun L, Rommens JM, Corvol H, Li W, Li X et al. 2012. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat. Genet. 44:562–69
    [Google Scholar]
  133. 133.  Swahn H, Stolzenburg L, Yang R, Lamar K, Kerschner JL et al. 2017. Regulatory role of chromosome 11p13 in cystic fibrosis lung disease severity. Pediatr. Pulmonol. 52:263
    [Google Scholar]
  134. 134.  Tanaka T, Goto K, Iino M 2017. Diverse functions and signal transduction of the exocyst complex in tumor cells. J. Cell. Physiol. 232:939–57
    [Google Scholar]
  135. 135.  Taylor C, Commander CW, Collaco JM, Strug LJ, Li W et al. 2011. A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies. Pediatr. Pulmonol. 46:857–69
    [Google Scholar]
  136. 136.  Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A et al. 2017. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N. Engl. J. Med. 377:2013–23
    [Google Scholar]
  137. 137.  Trouve P, Genin E, Ferec C 2017. In silico search for modifier genes associated with pancreatic and liver disease in cystic fibrosis. PLOS ONE 12:e0173822
    [Google Scholar]
  138. 138.  Vanscoy LL, Blackman SM, Collaco JM, Bowers A, Lai T et al. 2007. Heritability of lung disease severity in cystic fibrosis. Am. J. Respir. Crit. Care Med. 175:1036–43
    [Google Scholar]
  139. 139.  Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z et al. 2016. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol. Biol. Cell 27:424–33
    [Google Scholar]
  140. 140.  Wagenaar GT, Sengers RM, Laghmani el H, Chen X, Lindeboom MP et al. 2014. Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats. Am. J. Physiol. Lung Cell. Mol. Physiol. 307:L261–72
    [Google Scholar]
  141. 141.  Wainwright BJ, Scambler PJ, Schmidtke J, Watson EA, Law HY et al. 1985. Localization of cystic fibrosis locus to human chromosome 7cen-q22. Nature 318:384–85
    [Google Scholar]
  142. 142.  Wang L, Ko ER, Gilchrist JJ, Pittman KJ, Rautanen A et al. 2017. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Sci. Adv. 3:e1602096
    [Google Scholar]
  143. 143.  Wang Y, Zhang B, Zhang L, An L, Xu J et al. 2017. The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions. bioRxiv 112268. https://doi.org/10.1101/112268
    [Crossref]
  144. 144.  Wang YY, Lin YH, Wu YN, Chen YL, Lin YC et al. 2017. Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice. PLOS Genet 13:e1006715
    [Google Scholar]
  145. 145.  Weiler CA, Drumm ML 2013. Genetic influences on cystic fibrosis lung disease severity. Front. Pharmacol. 4:40
    [Google Scholar]
  146. 146.  Welsh MJ, Ramsey BW, Accurso FJ, Cutting GR 2001. Cystic fibrosis. The Metabolic and Molecular Bases of Inherited Disease D Valle, AL Beaudet, B Vogelstein, KW Kinzler, SE Antonarakis et al.5121–88 New York: McGraw-Hill
    [Google Scholar]
  147. 147.  Welsh MJ, Smith AE 1993. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73:1251–54
    [Google Scholar]
  148. 148.  Welter D, MacArthur J, Morales J, Burdett T, Hall P et al. 2014. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–6
    [Google Scholar]
  149. 149.  Wilschanski M, Novak I 2013. The cystic fibrosis of exocrine pancreas. Cold Spring Harb. Perspect. Med. 3:a009746
    [Google Scholar]
  150. 150.  Wilschanski M, Rivlin J, Cohen S, Augarten A, Blau H et al. 1999. Clinical and genetic risk factors for cystic fibrosis-related liver disease. Pediatrics 103:52–57
    [Google Scholar]
  151. 151.  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. 43:539–46
    [Google Scholar]
  152. 152.  Wright JM, Merlo CA, Reynolds JB, Zeitlin PL, Garcia JG et al. 2006. Respiratory epithelial gene expression in patients with mild and severe cystic fibrosis lung disease. Am. J. Respir. Cell Mol. Biol. 35:327–36
    [Google Scholar]
  153. 153.  Zielenski J 2000. Genotype and phenotype in cystic fibrosis. Respiration 67:117–33
    [Google Scholar]
  154. 154.  Zielenski J, Corey M, Rozmahel R, Markiewicz D, Aznarez I et al. 1999. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat. Genet. 22:128–29
    [Google Scholar]
  155. 155.  Zielenski J, Tsui L-C 1995. Cystic fibrosis: genotypic and phenotypic variations. Annu. Rev. Genet. 29:777–807
    [Google Scholar]
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