Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine

Abstract

Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.

Keywords: CFTR; GWAS; cystic fibrosis; modifier genes; phenotypic variability.

Figure 1

Genetic and non-genetic modifiers of phenotype in cystic fibrosis: the interaction between the CFTR genotype with modifier genes and environmental factors.

Figure 2

Heritability estimates for cystic fibrosis related phenotypes established from twins and sibling studies [74,85,87,88,89,90,91,92]. ^a refers to the heritability that is not due to differences in phenotype that occur across different CFTR mutations; ^b depending on the method used for evaluation; ^c in CF patients with two severe mutations and pancreatic insufficiency.

Figure 3

Possible candidate genes that modify the pulmonary phenotype and comorbidities associated with cystic fibrosis.

Figure 4

Pathogenic mechanisms correlated with the severity of CF lung disease.