Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes

Abstract

Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named "modifier genes", influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.

Keywords: CFTR (Cystic Fibrosis Transmembrane Regulator) modulator therapy; cystic fibrosis; environmental factors; modifiers genes.

Figure 1

Genetic modifiers of cystic fibrosis (CF) phenotypic traits. Schematic representation of genes identified by genome wide association studies (GWAS) and whole exome sequencing (WES) as associated with the heterogeneity of CF complications (lung disease severity, Pseudomonas. aeruginosa lung infection, meconium ileus susceptibility and CF-related diabetes). Abbreviations (alphabetic order): angiotensin II receptor type 2 (AGTR2), Apaf-1 interacting protein (APIP), ATPase H⁺/K⁺ transporting non-gastric alpha2 subunit (ATP12A), Caveolin 2 (CAV2), class II major histocompatibility complex (HLA Class II), cyclin dependent kinase 5 regulatory associated protein 1-like 1 (CDKAL1), cyclin dependent kinase inhibitor 2A/B (CDKN2A/B), Dynactin subunit 4 (DCTN4), Ets Homologous Factor (EHF), Interferon Related Developmental Regulator 1 (IFRD1), insulin-like growth factor-binding protein 2 (IGFBP2), mucin 4 (MUC4), mucin 20 (MUC20), prothymosin alpha (PTMA), serine protease 1 (PRSS1), solute carrier family 26 member 9 (SLC26A9), solute carrier family 6 member 14 (SLC6A14), solute carrier family 9 member A3 (SLC9A3), transcription factor 7-like 2 (TCF7L2) and Transmembrane channel like 6 (TMC6). Created with BioRender.com.