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. 2005 Jul;60(7):558–563. doi: 10.1136/thx.2004.031153

Genotype-phenotype correlation for pulmonary function in cystic fibrosis

J de Gracia 1, F Mata 1, A Alvarez 1, T Casals 1, S Gatner 1, M Vendrell 1, D de la Rosa 1, L Guarner 1, E Hermosilla 1
PMCID: PMC1747467  PMID: 15994263

Abstract

Background: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF).

Methods: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I–II/I–II, I–II/III–V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups.

Results: Seventy four patients were included in the study. Patients with genotype I–II/I–II had significantly lower current spirometric values (p<0.001), greater loss of pulmonary function (p<0.04), a higher proportion of end-stage lung disease (p<0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I–II/III, I–II/IV and I–II/V (p<0.001).

Conclusions: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival.

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Selected References

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  1. Arkwright P. D., Laurie S., Super M., Pravica V., Schwarz M. J., Webb A. K., Hutchinson I. V. TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax. 2000 Jun;55(6):459–462. doi: 10.1136/thorax.55.6.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boucher R. C. An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev. 2002 Dec 5;54(11):1359–1371. doi: 10.1016/s0169-409x(02)00144-8. [DOI] [PubMed] [Google Scholar]
  3. Casals T., De-Gracia J., Gallego M., Dorca J., Rodríguez-Sanchón B., Ramos M. D., Giménez J., Cisteró-Bahima A., Olveira C., Estivill X. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490–495. doi: 10.1111/j.0009-9163.2004.00265.x. [DOI] [PubMed] [Google Scholar]
  4. Casals T., Ramos M. D., Giménez J., Larriba S., Nunes V., Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365–370. doi: 10.1007/s004390050643. [DOI] [PubMed] [Google Scholar]
  5. Chillón M., Casals T., Mercier B., Bassas L., Lissens W., Silber S., Romey M. C., Ruiz-Romero J., Verlingue C., Claustres M. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475–1480. doi: 10.1056/NEJM199506013322204. [DOI] [PubMed] [Google Scholar]
  6. Fanen P., Clain J., Labarthe R., Hulin P., Girodon E., Pagesy P., Goossens M., Edelman A. Structure-function analysis of a double-mutant cystic fibrosis transmembrane conductance regulator protein occurring in disorders related to cystic fibrosis. FEBS Lett. 1999 Jun 11;452(3):371–374. doi: 10.1016/s0014-5793(99)00647-x. [DOI] [PubMed] [Google Scholar]
  7. Gan K. H., Veeze H. J., van den Ouweland A. M., Halley D. J., Scheffer H., van der Hout A., Overbeek S. E., de Jongste J. C., Bakker W., Heijerman H. G. A cystic fibrosis mutation associated with mild lung disease. N Engl J Med. 1995 Jul 13;333(2):95–99. doi: 10.1056/NEJM199507133330204. [DOI] [PubMed] [Google Scholar]
  8. Gibson Ronald L., Burns Jane L., Ramsey Bonnie W. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003 Oct 15;168(8):918–951. doi: 10.1164/rccm.200304-505SO. [DOI] [PubMed] [Google Scholar]
  9. Gilfillan A., Warner J. P., Kirk J. M., Marshall T., Greening A., Ho L. P., Hargreave T., Stack B., McIntyre D., Davidson R. P67L: a cystic fibrosis allele with mild effects found at high frequency in the Scottish population. J Med Genet. 1998 Feb;35(2):122–125. doi: 10.1136/jmg.35.2.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Highsmith W. E., Jr, Burch L. H., Zhou Z., Olsen J. C., Strong T. V., Smith T., Friedman K. J., Silverman L. M., Boucher R. C., Collins F. S. Identification of a splice site mutation (2789 +5 G > A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis. Hum Mutat. 1997;9(4):332–338. doi: 10.1002/(SICI)1098-1004(1997)9:4<332::AID-HUMU5>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  11. Hull J., Thomson A. H. Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax. 1998 Dec;53(12):1018–1021. doi: 10.1136/thx.53.12.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jentsch Thomas J., Stein Valentin, Weinreich Frank, Zdebik Anselm A. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002 Apr;82(2):503–568. doi: 10.1152/physrev.00029.2001. [DOI] [PubMed] [Google Scholar]
  13. Kerem E., Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol. 1996 Dec;22(6):387–395. doi: 10.1002/(SICI)1099-0496(199612)22:6<387::AID-PPUL7>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  14. Kerem E., Nissim-Rafinia M., Argaman Z., Augarten A., Bentur L., Klar A., Yahav Y., Szeinberg A., Hiba O., Branski D. A missense cystic fibrosis transmembrane conductance regulator mutation with variable phenotype. Pediatrics. 1997 Sep;100(3):E5–E5. doi: 10.1542/peds.100.3.e5. [DOI] [PubMed] [Google Scholar]
  15. Kerem E., Reisman J., Corey M., Canny G. J., Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992 Apr 30;326(18):1187–1191. doi: 10.1056/NEJM199204303261804. [DOI] [PubMed] [Google Scholar]
  16. Loubières Yann, Grenet Dominique, Simon-Bouy Brigitte, Medioni Jacques, Landais Paul, Férec Claude, Stern Marc. Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients. Chest. 2002 Jan;121(1):73–80. doi: 10.1378/chest.121.1.73. [DOI] [PubMed] [Google Scholar]
  17. McKone Edward F., Emerson Scott S., Edwards Karen L., Aitken Moira L. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 May 17;361(9370):1671–1676. doi: 10.1016/S0140-6736(03)13368-5. [DOI] [PubMed] [Google Scholar]
  18. Ratjen Felix, Döring Gerd. Cystic fibrosis. Lancet. 2003 Feb 22;361(9358):681–689. doi: 10.1016/S0140-6736(03)12567-6. [DOI] [PubMed] [Google Scholar]
  19. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  20. Rosenstein B. J., Cutting G. R. The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998 Apr;132(4):589–595. doi: 10.1016/s0022-3476(98)70344-0. [DOI] [PubMed] [Google Scholar]
  21. Rowntree Rebecca K., Harris Ann. The phenotypic consequences of CFTR mutations. Ann Hum Genet. 2003 Sep;67(Pt 5):471–485. doi: 10.1046/j.1469-1809.2003.00028.x. [DOI] [PubMed] [Google Scholar]
  22. Schechter M. S., Shelton B. J., Margolis P. A., Fitzsimmons S. C. The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States. Am J Respir Crit Care Med. 2001 May;163(6):1331–1337. doi: 10.1164/ajrccm.163.6.9912100. [DOI] [PubMed] [Google Scholar]
  23. Stern R. C., Doershuk C. F., Drumm M. L. 3849+10 kb C-->T mutation and disease severity in cystic fibrosis. Lancet. 1995 Jul 29;346(8970):274–276. doi: 10.1016/s0140-6736(95)92165-6. [DOI] [PubMed] [Google Scholar]
  24. Tsui L. C., Durie P. Genotype and phenotype in cystic fibrosis. Hosp Pract (1995) 1997 Jun 15;32(6):115-8, 123-9, 134, passim. doi: 10.1080/21548331.1997.11443512. [DOI] [PubMed] [Google Scholar]
  25. Vankeerberghen Anne, Cuppens Harry, Cassiman Jean-Jacques. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros. 2002 Mar;1(1):13–29. doi: 10.1016/s1569-1993(01)00003-0. [DOI] [PubMed] [Google Scholar]
  26. Welsh M. J., Smith A. E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993 Jul 2;73(7):1251–1254. doi: 10.1016/0092-8674(93)90353-r. [DOI] [PubMed] [Google Scholar]
  27. de Gracia J., Urrutia A., Guarga A., Joanmiquel L., Monso E., Vidal R. Fibrosis quística en el adulto. Med Clin (Barc) 1984 Sep 29;83(9):392–393. [PubMed] [Google Scholar]
  28. de Gracia Javier, Alvarez Antonio, Mata Fernando, Guarner Luisa, Vendrell Montserrat, Gadtner Silvia, Cobos Nicolás. Fibrosis quística del adulto: estudio de 111 pacientes. Med Clin (Barc) 2002 Nov 9;119(16):605–609. doi: 10.1016/s0025-7753(02)73513-6. [DOI] [PubMed] [Google Scholar]

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