Carriers of a single CFTR mutation are asymptomatic: an evolving dogma?
- 1Institut Cochin, Inserm U1016 and Université de Paris, Paris, France
- 2Dept of Respiratory Medicine and National Reference Center for Cystic Fibrosis Cochin Hospital, Assistance Publique, Hôpitaux de Paris, Paris, France
- Pierre-Régis Burgel, Dept of Respiratory Medicine, Cochin Hospital, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. E-mail: pierre-regis.burgel{at}aphp.fr
Abstract
CF carriers may be at higher risk of multiple CFTR-related diseases https://bit.ly/3foJK7n
Cystic fibrosis (CF) is a genetic autosomal recessive disease due to mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein [1, 2]. Mutations in the CFTR gene may cause a reduction of CFTR protein function, leading to abnormal chloride and bicarbonate transport in epithelia, resulting in abnormal mucus properties and a multiorgan disease dominated by respiratory and gastro-intestinal abnormalities [3]. The level of CFTR protein function is an important determinant of disease in humans and CF patients carrying two disease-causing CFTR mutations usually have very low levels of functional CFTR protein. Carriers of a single CFTR mutation (also called CF carriers) express 50% CFTR protein function, a level that has been considered sufficient to stay healthy [3]. CF carriers represent approximately 1 in 35 Caucasian in the USA, accounting for more than 10 million individuals [4]. CF carriers are generally informed that they are at risk of transmitting the mutation to their children and/or to have a child with CF; they are also informed that having one CFTR gene mutation does not cause symptoms [4]. Having a single CFTR mutation has even been suspected to provide a selective advantage, as CF carriers may withstand secretory diarrhoea better than non-carrier individuals, leading to a possible protection against cholera [5]. This latter finding has been suggested to explain the high rate of CF carriers in Caucasian populations [1].
Several studies have reported increased rates of CF carriers in cohorts of patients with bronchiectasis, chronic rhinosinusitis/nasal polyposis, or idiopathic chronic pancreatitis, questioning possible roles of a single CFTR mutation in the pathophysiology of these diseases (as reviewed previously [6]). In the present issue of the European Respiratory Journal, Çolak et al. [7] took the reverse approach: they hypothesised that CF carriers could be at higher risk of death or disease. The authors genotyped 108 035 randomly selected white Danish individuals from the Copenhagen General Population Study for the Phe508del CFTR mutation (the most prevalent CFTR mutation worldwide) and looked for morbidity and mortality, using questionnaires (for chronic bronchitis), spirometry and medico-administrative databases. The authors found 2858 (3%) carriers of a single Phe508del CFTR allele, corresponding to a prevalence of 1 in 38 subjects. Carriers and non-carriers of the Phe508del CFTR allele had comparable overall survival. However, carriers of the Phe508del CFTR allele had increased risk of chronic bronchitis (multivariable adjusted odds ratio of 1.31), bronchiectasis (multivariable adjusted hazard ratio of 1.88) and lung cancer (multivariable adjusted hazard ratio of 1.52). The authors also found that carriers of the Ph508del CFTR allele had non-significant trends for higher risk in chronic rhinosinusitis, spontaneous pneumothorax and male infertility (all of which are found in subjects with CF). However, they reported no association for respiratory failure, acute or chronic pancreatitis, liver cirrhosis, gastric or colorectal cancer.
The study by Çolak et al. [7] has some limitations: the authors limited the analysis to the most prevalent CFTR mutation (Phe508del), presumably in order to reduce the cost of the study. Although it is unlikely that an important number of CF carriers had a second disease-causing CFTR mutation (as most patients with CF are diagnosed and followed in Denmark) it appears possible that some people without a Phe508del CFTR mutation had another non Phe508del CFTR mutation. As these people would have been classified in the non-carrier group, the choice of limiting the analysis to carriers of the Phe508del mutation may have reduced the increased risk of disease attributed to carriers of a single CFTR mutation. Further, even in this large cohort study, the statistical significance of the associations could have been affected by the number of patients in the cohort, especially for rare disorders (e.g. chronic pancreatitis). The risk of misclassification, due to limitation of the study to Phe508del mutation, and the sample size may have accounted for some surprising results such as the non-significant association with chronic pancreatitis and colorectal cancer. The finding that lung cancer is increased in carrier of a Phe508del mutation is also surprising, because the risk of gastro-intestinal cancer, but not the risk of lung cancer, has been found increased in patients with CF [8]. However, the CF population is still relatively young and has usually low exposure to cigarette smoke, whereas patients in the present study were older and heavily exposed to cigarette smoke. This underlines the importance of controlling risk factors such as cigarette smoke in patients with CF, especially as ageing of the CF population is predicted in many countries [9].
The elegant data by Çolak et al. [7] provide an interesting complement to a recently published study by Miller et al. [10], who identified 19 802 CF carriers using a US administrative database and matched each carrier with five controls. The authors reported significantly increased risk for 57 conditions related to CF, including chronic bronchitis and bronchiectasis, male infertility, and pancreatitis [11]. Although there are methodological differences between these studies, which may account for some discrepancies in the results (for example the increased risk of pancreatitis was significant in the study by Miller et al. [10] but not in the present study by Çolak et al. [7]), both studies challenge the dogma that CF carriers are asymptomatic. Indeed, both studies reported increased relative risk of multiple diseases in CF carriers compared with non-carriers. Importantly, the absolute risk of disease remained low in both studies [7, 10], indicating that most CF carriers will indeed remain asymptomatic [10, 12]. For example, only 322/2858 (11.2%) carriers of the Phe508del mutation developed chronic bronchitis in the study by Çolak et al. [7]. Even when looking at the risk of multiple diseases, as in the study by Miller et al. [10], only a minority of CF carriers developed at least one of these diseases [10].
The studies by Çolak et al. [7] and Miller et al. [10] provide epidemiological evidence of increased risk of multiple diseases (most often related to respiratory, gastro-intestinal and pancreatic systems) in CF carriers. Interestingly, several studies provide biological plausibility for these findings by linking CF carriers to specific biological abnormalities. Epithelial chloride transport appeared abnormal in CF carriers, as evidenced by higher than normal sweat chloride concentration [13], and by abnormal nasal potential difference measurements in CF carriers with bronchiectasis as compared to patients with bronchiectasis but no CFTR mutation [14]. Data obtained in newborn screening programmes have reported higher blood immunoreactive trypsinogen concentrations in CF carriers compared to normal [15, 16], indicating pancreatic abnormalities. Moriceau et al. [17] discovered that both children with CF and their parents, who are obligate heterozygotes for CFTR mutations, demonstrated delayed neutrophil apoptosis compared with healthy controls. Recent evidence further suggests that CFTR dysfunction could also be acquired: exposure to cigarette smoking could induce CFTR dysfunction in airway epithelium [18] and systemically [19]; viral infection [20], bacterial products [21] and neutrophil proteases [22] could also result in defective CFTR function. Epigenetic CpG island hypermethylation of the CFTR gene turns off its transcriptional expression [11]. Thus, it appears possible that CF carriers have reduced CFTR protein function at birth and that environmental exposures/epigenetic regulation may result in further reduction of CFTR protein function, leading to disease in selected patients. It is also possible that multiple gene defects could contribute to disease in CF carriers. For example, it has been suggested that combination of mutations in the epithelial sodium channel (ENaC) gene and in the CFTR gene predispose to bronchiectasis with abnormal epithelial ion transport [23]. This hypothesis, which is represented in figure 1, would explain why only a subset of CF carriers develop disease, whereas most CF carriers remain asymptomatic.
Findings by Çolak et al. [7] and Miller et al. [10] clearly change the dogma that CF carriers are always asymptomatic, and these studies may have important consequences. First, the number of people diagnosed as CF carriers will likely continue to increase as genetic testing is now increasingly proposed for cascade screening of a relative of a CF case, for preconception screening in selected populations, and as systematic screening in some geographical areas [24]. Further, the implementation of newborn screening programmes in multiple countries is associated with the detection of eight to ten CF carriers per each diagnosed case of CF [25]. Thus, findings that CF carriers may be at increased risk of diseases represent a challenge for discussing with CF carriers: it may not be any longer appropriate to consider that these patients have no risk of disease, yet most of them will indeed remain asymptomatic. This findings highlight the difficulty in making individual prediction based on the presence of a single mutation in a gene associated with a recessive disorder, but also provide an opportunity for preventative medicine by advising a healthy lifestyle, as the consequences of environmental exposures (e.g. cigarette smoking) could prove even more deleterious in CF carriers. Second, the recent development of highly effective CFTR modulators (especially for CF patients with at least one Phe508del allele [26, 27]) provides the opportunity of repositioning CFTR modulators for airway diseases other than CF [28]. The development of CFTR modulator for the treatment of patients with COPD and chronic bronchitis appears of particular interest [29]. The high population attributable risk of bronchiectasis for CF carriers [12] also warrants further interest, as a proportion of patients with non-CF bronchiectasis may derive benefit from CFTR modulators. The findings that loss of normal CFTR activity leads to activation of tyrosine kinase receptors [30] and that CFTR may suppress cancer [31] could also provide a rationale for the repositioning of CFTR modulators for the treatment of cancer (e.g. colon cancer [29]).
In summary, the data presented by Çolak et al. [7] contribute to further challenging the dogma that CF carriers are strictly asymptomatic. The results provide opportunities for rethinking the relationship of a single CFTR mutation to individual risk prediction and strengthens the rationale for repositioning CFTR modulators for the treatment of diseases other than CF. For all these reasons, the authors should be congratulated for their nice report.
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Footnotes
Conflict of interest: C. Martin reports personal fees from Vertex and Zambon, outside the submitted work.
Conflict of interest: P-R. Burgel reports personal fees for advisory board work and lectures from AstraZeneca, Chiesi, GSK, Novartis, Teva and Vertex, grants and personal fees for advisory board work and lectures from Boehringer Ingelheim, personal fees for advisory board work from Zambon, personal fees for lectures from Pfizer, outside the submitted work.
- Received July 5, 2020.
- Accepted July 6, 2020.
- Copyright ©ERS 2020