Abstract
Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.
Highlights
Cystic fibrosis (CF) is an autosomal recessive inherited disorder affecting at least70,000 people worldwide
Many modifier gene studies have been conducted; here, we focus on the most significant of these and consider the evidence for the role of non-genetic modifiers (Figure 1)
In 2010, a study looking at mutations in Endothelin receptor type A (EDNRA) among four different cohorts found that the CC genotype in rs5335 was associated with a 5% absolute reduction in lung function [38]
Summary
Cystic fibrosis (CF) is an autosomal recessive inherited disorder affecting at least. It is caused by a mutation in the Cystic Fibrosis Transmembrane. The consequence of CFTR dysfunction is the disruption of normal ion transport across cell surfaces, leading to thick, sticky mucus in the respiratory, reproductive and digestive tracts [1]. In the lungs, this leads to bacterial infection, inflammation [2], airway scarring (bronchiectasis) [3] and early mortality from respiratory failure. CFTR protein reaches the cell membrane but defect in channel gating, e.g., S549R, G551D, G1349D. CFTR protein reaches the cell membrane but there is defective conductance, e.g., R117H, R334W, D1152H. CFTR protein is produced and is in the correct location but has reduced stability with rapid turnover, e.g., F508del, Q1411X
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