**3. Influence of genotype on prognosis in cystic fibrosis**

CF is the most common lethal genetic disease of Caucasian populations and is caused by genetic mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. The CFTR gene encodes an ATP- and CAMP-dependent chloride channel expressed on the apical membrane of epithelial and certain non-epithelial cells throughout the body. To date, greater than 1,000 CFTR mutations have been discovered. In the lung, it also regulates the activity of the ENaC channel (an apical sodium transport channel) defects in which mediate the majority of pathogenic processes in the main target organ in CF sufferers.

Commonly, the multitude of various CFTR mutations are classified into 6 distinct groups based on their ultimate effects on a range of cellular mechanisms such as transcription, processing within the cell, localization of the channel, and quantity of correctly functioning protein. Class I includes mutations with complete lack of production of protein while Class VI involves unstable functional protein being produced that is then degraded at the cell surface (Table 1).


**Table 1.** List of CFTR Mutations.

The most common CFTR mutation worldwide is delF508 that accounts for upwards of 70% of cases of CF and has long been associated with more severe disease and less favourable clinical outcomes [15-17]. Conversely, several mutations have been found to be associated with more favourable outcomes and milder clinical phenotypes. In a study based on the US CF Registry in 2003, it was found that significantly different mortality rates were observed when CFTR genotype was classified according to the effects on quantitative protein production. The authors proposed that groups with severely reduced levels of CFTR (I-III) had a more severe clinical phenotype and higher mortality than groups with some residual CFTR function (IV-VI) [18]. A follow up study found that 'high risk' patients (I-III) had a two-fold greater risk of death when compared to 'low risk' (IV-VI) patients [19] and this risk was not fully explained by lung function, pancreatic insufficiency, *Pseudomonas aeruginosa* (PA) colonisation, or nutritional factors. Hence, CFTR genotype may be useful as an initial measure of prognosis in early CF diagnosis when it is often the only available information about the disease. Knowl‐ edge of the genetic processes involved in CF is leading the way for new targeted therapies that ideally will improve mortality. One such therapy is ivacaftor, a potentiator drug that enhances gating at the cell surface in patients with the class III G551D mutation. This novel medication has been associated with sustained increases in FEV1 of up to 10%, reduced frequency of pulmonary exacerbation, weight gain, and subjective improvements in quality of life (CFQ-R) scores [4, 20, 21]. However, there is wide phenotypic variance observed frequently among patients with identical genotypes. This is observed in the clinical realms of lung function, pancreatic and diabetic status, nutritional status, and response to medications and this leads to reluctance to link genotype too closely with phenotype in terms of predicting clinical outcomes and prognosis.
