Update on gene modifiers in cystic fibrosis

Abstract

Purpose of review Cystic fibrosis (CF) is a common, life-limiting monogenic disease, which typically manifests as progressive bronchiectasis, exocrine pancreatic dysfunction, and recurrent sinopulmonary infections. Although the gene responsible for CF (CFTR) was described in 1989, it has become increasingly evident that modifier genes and environmental factors play substantial roles in determining the severity of disease, particularly lung disease. Identifying these factors is crucial in devising therapies and other interventions to decrease the morbidity and mortality associated with this disorder. Recent findings Although many genes have been proposed as potential modifiers of CF, only a handful have withstood the test of replication. Several of the replicated findings reveal that genes affecting inflammation and infection response play a key role in modifying CF lung disease severity. Interactions between CFTR genotype, modifier genes, and environmental factors have been documented to influence lung function measures and infection status in CF patients. Summary Several genes have been demonstrated to affect disease severity in CF. Furthermore, it is likely that gene–gene and gene–environment interactions can explain a substantial portion of the variation of lung disease. Ongoing genome-wide studies are likely to identify novel genetic modifiers. Continued exploration of the role of genetic and nongenetic modifiers of CF is likely to yield new options for combating this debilitating disease.

Cystic Fibrosis Carrier Testing in an Ethnically Diverse US Population

“…Similarly, other mutations identified in carriers of 2 mutations have been associated with variable phenotypic expression ranging from classic disease to CBAVD in adults or an asymptomatic phenotype when identified in the neonatal period (24 -28 ). In general, the phenotypic variability in CF is substantial and is due to the CFTR genotype, as well as to other genetic modifiers, environmental factors, and their interactions (38,39 ). Recognizing the limited predictability of the CF clinical presentation from the CFTR genotype, the ACMG has recommended discussion of these limitations during genetic counseling and the informedconsent process (21 ).…”

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

“…Polymorphisms at codon 10 and 25 up-regulate TGF-␤1 synthesis (11). These TGF-␤1 genotypes have been associated with worse lung function in at least three independent large clinical studies (12). Furthermore, bronchoalveolar lavage fluid levels of TGF-␤1 were elevated in CF patients and associated with diminished lung function and recent hospitali-zation (13).…”

Gene Therapy of Some Genetic Diseases by Transferring Normal Human Genomic DNA into Somatic Cells and Stem Cells from Patients

“…Cystic fibrosis affacts more than 70, 000 individuals worldwide. In 2006, the median survival age for a person with cystic fibrosis was 37 (M. Anderson et al, 1991;Collaco & Cutting, 2008;Collins, 1992;Cutting, 2010;Lee et al, 2005;Rowntree & Harris, 2003;G. Wang et al, 2005;Zielenski, 2000).…”