Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes

Am J Med Genet. 2002 Jul 22;111(1):88-95. doi: 10.1002/ajmg.10461.


More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Codon, Nonsense
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / biosynthesis
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Epistasis, Genetic*
  • Gene Expression Regulation
  • Genetic Heterogeneity
  • Genotype
  • Humans
  • Intestinal Obstruction / etiology
  • Liver / metabolism
  • Liver / pathology
  • Lung / metabolism
  • Lung / pathology
  • Meconium
  • Mice
  • Mice, Inbred CFTR
  • Multifactorial Inheritance
  • Mutation
  • Organ Specificity
  • Pancreas / metabolism
  • Pancreas / pathology
  • Phenotype
  • Polymorphism, Genetic


  • CFTR protein, human
  • Codon, Nonsense
  • Cystic Fibrosis Transmembrane Conductance Regulator