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Phenotypic Factors: CFTR activity is an important influence on cystic fibrosis phenotype

Although loss of CFTR activity causes cystic fibrosis (CF) disease, several factors influence the clinical phenotype in individuals with CF. These factors contribute to the variability of symptoms among patients. Phenotypic expression is affected by1-5:

  • CFTR genotype and total CFTR activity: CFTR genotype determines the quantity and function of CFTR proteins, which in turn determines total CFTR activity at the cell surface1,2,5-9
    • Generally, the presence of mutations that produce little to no CFTR activity on both CFTR alleles are associated with early evidence of disease progression
    • Having a mutation that produces residual CFTR activity may be associated with delayed onset of symptoms and progression
    • Complex alleles may also contribute to reduction in total CFTR activity (e.g., the length of the polythymidine tract influences the effect the R117H mutation has on CFTR protein activity)
  • Modifier genes: may affect lung function and disease course2,3
    • Examples include key factors of the immune system, mannose-binding lectin 2 (MBL2) and transforming growth factor-beta 1 (TGF-ß1)
  • Environmental factors: can significantly affect phenotype. Examples may include1-4,10:
    • Level of care/socioeconomic status
    • Nutritional status
    • Exposure to cigarette smoke and other pollutants
    • Age at onset of lung infection

Factors that influence CF phenotype

Several factors influence CF clinical phenotype, including genotype, CFTR activity, modifier genes, and environmental factors

Learn more about how total CFTR activity affects phenotype.

  1. Castellani C, Cuppens H, Macek M, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-196.
  2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117‐133.
  3. Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012;2(12):1-13.
  4. Quittner AL, Schechter MS, Rasouliyan L, Haselkorn T, Pasta DJ, Wagener JS. Impact of socioeconomic status, race, and ethnicity on quality of life in patients with cystic fibrosis in the United States. Chest. 2010;137(3):642-650.
  5. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993;362(6416):160-164.
  6. Green DM, McDougal KE, Blackman SM, et al. Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res. 2010;11(140). doi:10.1186/1465-9921-11-140.
  7. Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med. 1993;329(18):1308-1313.
  8. McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003;361(9370):1671-1676.
  9. Kiesewetter S, Macek M Jr, Davis C, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993;5(3):274-278.
  10. Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr. 2007;151(2):134-139.