PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jrsocmedLink to Publisher's site
 
J R Soc Med. 2005; 98(Suppl 45): 47–54.
PMCID: PMC1308808

Cystic fibrosis modifier genes.

Abstract

Since the recognition that CFTR genotype was not a good predictor of pulmonary disease severity in CF, several candidate modifier genes have been identified. It is unlikely that a single modifier gene will be found, but more probable that several haplotypes in combination may contribute, which in itself presents a major methodological challenge. The aims of such studies are to increase our understanding of disease pathogenesis, to aid prognosis and ultimately to lead to the development of novel treatments.

Full Text

The Full Text of this article is available as a PDF (89K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • 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. [PubMed]
  • Santis G, Osborne L, Knight RA, Hodson ME. Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis. Lancet. 1990 Nov 3;336(8723):1081–1084. [PubMed]
  • Kerem E, Corey M, Kerem BS, Rommens J, Markiewicz D, Levison H, Tsui LC, Durie P. The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508). N Engl J Med. 1990 Nov 29;323(22):1517–1522. [PubMed]
  • Bronsveld I, Mekus F, Bijman J, Ballmann M, de Jonge HR, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, et al. Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. J Clin Invest. 2001 Dec;108(11):1705–1715. [PMC free article] [PubMed]
  • Chen X, Sullivan PF. Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput. Pharmacogenomics J. 2003;3(2):77–96. [PubMed]
  • Rubinsztein DC, Easton DF. Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis. Dement Geriatr Cogn Disord. 1999 May-Jun;10(3):199–209. [PubMed]
  • Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000 Sep;26(1):76–80. [PubMed]
  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599–603. [PubMed]
  • Sato Hiroe, Grutters Jan C, Pantelidis Panagiotis, Mizzon A Neil, Ahmad Tariq, Van Houte Arend-Jan, Lammers Jan-Willem J, Van Den Bosch Jules M M, Welsh Kenneth I, Du Bois Roland M. HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol. 2002 Oct;27(4):406–412. [PubMed]
  • Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Hotta M, Ueda H, Shintani M, Nojima K, Ono M, Nishino M, et al. Age-related association of MHC class I chain-related gene A (MICA) with type 1 (insulin-dependent) diabetes mellitus. Hum Immunol. 2000 Jun;61(6):624–629. [PubMed]
  • Iacopetta B, Grieu F, Joseph D. The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype. Br J Cancer. 2004 Jan 26;90(2):419–422. [PMC free article] [PubMed]
  • Boekholdt S Matthijs, Peters Ron J G, de Maat Moniek P M, Zwinderman Aeilko H, van Der Wall Ernst E, Reitsma Pieter H, Jukema J Wouter, Kastelein John J P. Interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. Am Heart J. 2004 Jan;147(1):181–186. [PubMed]
  • Goetz Matthew P, Ames Matthew M, Weinshilboum Richard M. Primer on medical genomics. Part XII: Pharmacogenomics--general principles with cancer as a model. Mayo Clin Proc. 2004 Mar;79(3):376–384. [PubMed]
  • Koch C, Høiby N. Pathogenesis of cystic fibrosis. Lancet. 1993 Apr 24;341(8852):1065–1069. [PubMed]
  • Döring G, Krogh-Johansen H, Weidinger S, Høiby N. Allotypes of alpha 1-antitrypsin in patients with cystic fibrosis, homozygous and heterozygous for deltaF508. Pediatr Pulmonol. 1994 Jul;18(1):3–7. [PubMed]
  • Mahadeva R, Lomas DA. Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema. Thorax. 1998 Jun;53(6):501–505. [PMC free article] [PubMed]
  • Mahadeva R, Westerbeek RC, Perry DJ, Lovegrove JU, Whitehouse DB, Carroll NR, Ross-Russell RI, Webb AK, Bilton D, Lomas DA. Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease. Eur Respir J. 1998 Apr;11(4):873–879. [PubMed]
  • Mahadeva R, Sharples L, Ross-Russell RI, Webb AK, Bilton D, Lomas DA. Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis. Thorax. 2001 Jan;56(1):53–58. [PMC free article] [PubMed]
  • Mahadeva R, Stewart S, Bilton D, Lomas DA. Alpha-1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease. Thorax. 1998 Dec;53(12):1022–1024. [PMC free article] [PubMed]
  • Henry MT, Cave S, Rendall J, O'Connor CM, Morgan K, FitzGerald MX, Kalsheker N. An alpha1-antitrypsin enhancer polymorphism is a genetic modifier of pulmonary outcome in cystic fibrosis. Eur J Hum Genet. 2001 Apr;9(4):273–278. [PubMed]
  • Frangolias Despina D, Ruan Jian, Wilcox Pearce J, Davidson A George F, Wong Lawrence T K, Berthiaume Yves, Hennessey Rosamund, Freitag Andreas, Pedder Linda, Corey Mary, et al. Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):390–396. [PubMed]
  • Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D. HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype. Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1464–1468. [PubMed]
  • Aron Y, Bienvenu T, Hubert D, Dusser D, Dall'Ava J, Polla BS. HLA-DR polymorphism in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1999 Oct;104(4 Pt 1):891–892. [PubMed]
  • Greally P, Hussein MJ, Cook AJ, Sampson AP, Piper PJ, Price JF. Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis. Arch Dis Child. 1993 Mar;68(3):389–392. [PMC free article] [PubMed]
  • Hull J, Thomson AH. Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax. 1998 Dec;53(12):1018–1021. [PMC free article] [PubMed]
  • Arkwright Peter D, Pravica Vera, Geraghty Philip J, Super Maurice, Webb A Kevin, Schwarz Martin, Hutchinson Ian V. End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. Am J Respir Crit Care Med. 2003 Feb 1;167(3):384–389. [PubMed]
  • Grasemann H, Knauer N, Büscher R, Hübner K, Drazen JM, Ratjen F. Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med. 2000 Dec;162(6):2172–2176. [PubMed]
  • Grasemann Hartmut, Storm van's Gravesande Karin, Buscher Rainer, Knauer Nicola, Silverman Eric S, Palmer Lyle J, Drazen Jeffrey M, Ratjen Felix. Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003 Feb 1;167(3):390–394. [PubMed]
  • Förstermann U, Boissel JP, Kleinert H. Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J. 1998 Jul;12(10):773–790. [PubMed]
  • Accurso Frank J, Sontag Marci K. Seeking modifier genes in cystic fibrosis. Am J Respir Crit Care Med. 2003 Feb 1;167(3):289–290. [PubMed]
  • Mekus Frauke, Tümmler Burkhard. Cystic fibrosis and NOS3. Am J Respir Crit Care Med. 2004 Jan 15;169(2):319–320. [PubMed]
  • Arkwright PD, Laurie S, Super M, Pravica V, Schwarz MJ, Webb AK, Hutchinson IV. TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax. 2000 Jun;55(6):459–462. [PMC free article] [PubMed]
  • Wojnarowski C, Frischer T, Hofbauer E, Grabner C, Mosgoeller W, Eichler I, Ziesche R. Cytokine expression in bronchial biopsies of cystic fibrosis patients with and without acute exacerbation. Eur Respir J. 1999 Nov;14(5):1136–1144. [PubMed]
  • Turner MW. The role of mannose-binding lectin in health and disease. Mol Immunol. 2003 Nov;40(7):423–429. [PubMed]
  • Garred P, Pressler T, Madsen HO, Frederiksen B, Svejgaard A, Høiby N, Schwartz M, Koch C. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest. 1999 Aug;104(4):431–437. [PMC free article] [PubMed]
  • Gabolde M, Guilloud-Bataille M, Feingold J, Besmond C. Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. BMJ. 1999 Oct 30;319(7218):1166–1167. [PMC free article] [PubMed]
  • Garred Peter, Pressler Tacjana, Lanng Susanne, Madsen Hans O, Moser Claus, Laursen Inga, Balstrup Flemming, Koch Claus, Koch Christian. Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease. Pediatr Pulmonol. 2002 Mar;33(3):201–207. [PubMed]
  • Ramsay CE, Hayden CM, Tiller KJ, Burton PR, Goldblatt J, Lesouef PN. Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy. 1999 Sep;29(9):1195–1203. [PubMed]
  • Taouil Karima, Hinnrasky Jocelyne, Hologne Coralie, Corlieu Pascal, Klossek Jean-Michel, Puchelle Edith. Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane conductance regulator expression in human airway epithelial cells through a cAMP/protein kinase A-independent pathway. J Biol Chem. 2003 May 9;278(19):17320–17327. [PubMed]
  • Büscher Rainer, Eilmes Katrin Jennifer, Grasemann Hartmut, Torres Brian, Knauer Nicola, Sroka Karin, Insel Paul A, Ratjen Felix. beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics. 2002 Jul;12(5):347–353. [PubMed]
  • Eggermont E. Gastrointestinal manifestations in cystic fibrosis. Eur J Gastroenterol Hepatol. 1996 Aug;8(8):731–738. [PubMed]
  • Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, et al. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet. 1996 Mar;12(3):280–287. [PubMed]
  • Zielenski J, Corey M, Rozmahel R, Markiewicz D, Aznarez I, Casals T, Larriba S, Mercier B, Cutting GR, Krebsova A, et al. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet. 1999 Jun;22(2):128–129. [PubMed]
  • Duthie A, Doherty DG, Donaldson PT, Scott-Jupp R, Tanner MS, Eddleston AL, Mowat AP. The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis. J Hepatol. 1995 Nov;23(5):532–537. [PubMed]
  • Gabolde M, Hubert D, Guilloud-Bataille M, Lenaerts C, Feingold J, Besmond C. The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis. J Med Genet. 2001 May;38(5):310–311. [PMC free article] [PubMed]
  • Mekus Frauke, Laabs Ulrike, Veeze Henk, Tümmler Burkhard. Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum Genet. 2003 Jan;112(1):1–11. [PubMed]
  • Noone PG, Pue CA, Zhou Z, Friedman KJ, Wakeling EL, Ganeshananthan M, Simon RH, Silverman LM, Knowles MR. Lung disease associated with the IVS8 5T allele of the CFTR gene. Am J Respir Crit Care Med. 2000 Nov;162(5):1919–1924. [PubMed]
  • Groman Joshua D, Hefferon Timothy W, Casals Teresa, Bassas Lluís, Estivill Xavier, Des Georges Marie, Guittard Caroline, Koudova Monika, Fallin M Daniele, Nemeth Krisztina, et al. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet. 2004 Jan;74(1):176–179. [PubMed]
  • Cuppens H, Lin W, Jaspers M, Costes B, Teng H, Vankeerberghen A, Jorissen M, Droogmans G, Reynaert I, Goossens M, et al. Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest. 1998 Jan 15;101(2):487–496. [PMC free article] [PubMed]
  • Dörk T, Wulbrand U, Richter T, Neumann T, Wolfes H, Wulf B, Maass G, Tümmler B. Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene. Hum Genet. 1991 Aug;87(4):441–446. [PubMed]
  • Romey MC, Guittard C, Chazalette JP, Frossard P, Dawson KP, Patton MA, Casals T, Bazarbachi T, Girodon E, Rault G, et al. Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone. Hum Genet. 1999 Jul-Aug;105(1-2):145–150. [PubMed]
  • Morgan TM, Coffey CS, Krumholz HM. Overestimation of genetic risks owing to small sample sizes in cardiovascular studies. Clin Genet. 2003 Jul;64(1):7–17. [PubMed]
  • Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan PD. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol. 1996 May;21(5):267–275. [PubMed]
  • Romieu I, Sienra-Monge JJ, Ramírez-Aguilar M, Moreno-Macías H, Reyes-Ruiz NI, Estela del Río-Navarro B, Hernández-Avila M, London SJ. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City. Thorax. 2004 Jan;59(1):8–10. [PMC free article] [PubMed]
  • Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. [PubMed]
  • Boyle Michael P. Nonclassic cystic fibrosis and CFTR-related diseases. Curr Opin Pulm Med. 2003 Nov;9(6):498–503. [PubMed]

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press