**4. Impact of gender on prognosis**

in assessing outcomes. As such, a "one size fits all" approach to prognosticating is not appropriate. In this chapter, we review the evidence regarding prognosis based on key clinical and demographic parameters, and the biomarkers and prediction tools that may be used to

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

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).

nonsense; splicing; deletions

insertions

insertions

insertions

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

W128X; R553X; G542X

G551D; G551S; G1349D

R117H; R334W, R347P

Missense; nonsense 120del23; N287Y; 4279insA

F508del; N1303K

**Class Effect Mutation Type Example**

**I** No functional protein produced Premature stop codons:

**II** Defective processing and maturation Missense; small deletions or

**III** Defects in regulation of channel opening Missense; small deletions or

**IV** Defective Chloride transport Missense; small deletions or

**VI** Increased turnover of unstable protein at cell

surface

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

**V** Reduction of wild-type mRNA Partial splicing A455E

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

pathogenic processes in the main target organ in CF sufferers.

predict outcome.

6 Cystic Fibrosis in the Light of New Research

It has long been recognized that there is a significant gender difference in terms of both morbidity and mortality in cystic fibrosis. Many studies, throughout early and current cystic fibrosis research, have focused on the poorer outcomes observed in female patients when compared with their male counterparts. This dichotomy endures across the areas of microbial colonization, lung function, frequency of exacerbations, and overall survival. However, an explanation for this vast difference remains to be found.

A notable early study conducted in Canada investigated the effects of numerous variables on mortality and found that on average, males had overall increased survival rates of greater than 5 years when compared with female cohorts from the same time period (1970-1989) [22]. These results were echoed across international cohorts for similar time frames and were postulated to relate to the lower bone mineral density observed in female populations. Over time, as survival in cystic fibrosis increased, this gender difference has persisted with Rosenfeld et al. in 1997 confirming a gender difference in CF survival (25.3 vs. 28.4 females vs. males) in a cohort of over 20,000 patients [23], and Harness-Brumley et al. in more recent 2014 study observed this difference in greater than 32,000 North American patients (36.0 years vs. 38.7 years, females vs. males) [24]. Despite accounting for variables known to influence CF-related mortality, it was demonstrated that female gender is an independent significant risk factor for death. Furthermore, women were found to be colonized at an earlier age with various pathogens and that their clinical course was much worse when colonized with common CF pathogens [24].

Though the relationship between gender and adverse outcomes has been described in a multitude of studies over a vast period of time, a full explanation of this dichotomy remains elusive. Much current research now centres on the role of estrogen in female CF patients. The primary female sex hormone is 17β-estradiol (E2) and circulates in the body bound to sex hormone binding globulin, interacting with target tissues through a range of estrogen receptors (ERs) expressed on the cell surface. E2 levels naturally vary over the course of the normal menstrual cycle and E2 further dehydrates the already compromised airway surface liquid seen in CF and peak levels of E2 lead to an increased risk of infection and subsequent exacerbation [25]. Furthermore, high levels of E2 have been shown to promote TLR hypores‐ ponsiveness to a range of bacteria driven by an inhibition of interleukin-8 (IL-8) release [26]. In a study targeted to investigate the effects of E2 on *Pseudomonas Aeruginosa* (PA). it was found that high levels of E2 promotes mucoid conversion, alginate synthesis, and genetic mutations in mucins lending increased infectivity and virulence to PA in those exposed to E2 [15]. An interesting addendum to this study was the observation that the individuals studied had lower rates of exacerbation and required a lower number of antibiotic courses if they were using the combined oral contraceptive pill [15]. As exacerbation rate is commonly quoted as a predictor for mortality, there is scope here to assess the role of targeted estrogen therapies on mortality and the gender dichotomy in CF.
