Impact of Gene Modifiers on Cystic Fibrosis Phenotypic Profiles: A Systematic Review

Abstract

Cystic fibrosis (CF) is a complex monogenic disorder with a large variability in disease severity. Growing evidence suggests that the variation observed depends not only on variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but also on modifier genes. Utilizing five databases (including CINAHL, PubMed, Science Direct, Scopus, and Web of Science), a systematic review was conducted to examine the current literature on the known impacts of genomic variations in modifier genes on the CF disease progression, severity, and therapeutic response. A total of 70 full-text articles describing over 80 gene modifiers associated with CF were selected. The modifier genes included genes associated with the CFTR interactome, the inflammatory response, microbial profiles, and other genes affecting the critical physiological pathways of multiple organ systems, such as the respiratory and gastrointestinal systems. Limitations of the existing literature embrace the lack of clinical studies investigating pharmacogenetic impacts and the significance of gene modifiers on the CF clinical picture, including a limited number of replication and validation studies. Further investigations into other potential gene modifiers using genome-wide association studies are needed to critically explore new therapeutic targets and provide a better understanding of the CF disease phenotype under specific drug treatments.