Gene modifiers of cystic fibrosis lung disease: A systematic review

Abstract

Background Lung disease is the major source of morbidity and mortality in cystic fibrosis (CF), with large variability in severity between patients. Although accurate prediction of lung disease severity would be extremely useful, no robust methods exist. Twin and sibling studies have highlighted the importance of non‐cystic fibrosis transmembrane conductance regulator (CFTR) genes in determining lung disease severity but how these impact on the severity in CF remains unclear. Methods A systematic review was undertaken to answer the question “In patients with CF which non‐CFTR genes modify the severity of lung disease?” The method for this systematic review was based upon the “Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)” statement, with a narrative synthesis of results planned. Results A total of 1168 articles were screened for inclusion, with 275 articles undergoing detailed assessment for inclusion. One hundred and forty articles were included. Early studies focused on candidate genes, whereas more recent studies utilized genome‐wide approaches and also examined epigenetic mechanisms, gene expression, and therapeutic response. Discussion A large body of evidence regarding non‐CFTR gene modifiers of lung disease severity has been generated, examining a wide array of genes. Limitations to existing studies include heterogeneity in outcome measures used, limited replication, and relative lack of clinical impact. Future work examining non‐CFTR gene modifiers will have to overcome these limitations if gene modifiers are to have a meaningful role in the care of patients with CF.

Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function

“…This observation has led to the hypothesis that additional genetic loci likely contribute to pathophysiology of CF disease. Several studies have identified polymorphisms in genes related to innate immune function that appear to alter CF disease severity, including MUC4/MUC20, SLC9A3, SLC26A9, HLA Class II, AGTR2/SLC6A14, IFRD1, DCTN4, and EHF/APIP [4].…”

Characterization of clinical and genetic spectrum of Chinese patients with cystic fibrosis

“…It has been well known that the severity of CF lung disease varies dramatically even in patients with identical CFTR genotypes, in which genetic factors play an important role. [21][22][23] A review collected recent efforts aiming at identifying non-CFTR modifier genes for lung disease severity in cystic fibrosis. [21] Genotyping of reported modifier loci showed that patient 6 − 1 carried several risk alleles in the TGFB1, MUC4/MUC20 and HLA Ⅱ genes but patient 6 − 2 did not; the rest loci turned out to be the same for the siblings (Table S1).…”

“…[21][22][23] A review collected recent efforts aiming at identifying non-CFTR modifier genes for lung disease severity in cystic fibrosis. [21] Genotyping of reported modifier loci showed that patient 6 − 1 carried several risk alleles in the TGFB1, MUC4/MUC20 and HLA Ⅱ genes but patient 6 − 2 did not; the rest loci turned out to be the same for the siblings (Table S1). The TGFB1 codon 10 CC genotype (rs1800470) detected in patient 6 − 1 was reported to be related to severe lung function with an odds ratio of about 2.2.…”

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

“…Despite the identification of the CFTR gene and the growing mutation database, establishing a correlation between CF genotype and clinical phenotype remains difficult, considering the vastly different disease courses between patients, even between twin siblings sharing the same CFTR mutations ( Kerem et al, 1990 ; Mekus et al, 2000 ). Genome-wide association studies with large patient cohorts have identified genetic variants of specific loci associated with disease severity, called CF modifier genes, that contribute to phenotypic variability [see recent reviews ( Lim et al, 2018 ; Shanthikumar et al, 2019 )]. Among the proteins encoded by the CF modifier genes, some have direct protein-protein interaction with CFTR and/or are involved in immune response ( Tugores et al, 2001 ; Wright et al, 2011 ; Stanke et al, 2014 ; Corvol et al, 2015 ).…”