By Kelly Bonnville
If you’ve ever seen “Five Feet Apart”, a 2019 movie starring Cole Sprouse and Haley Lu Richardson, which tells the dramatic love story of two teenaged cystic fibrosis patients who can never be together due to their disease, you may be under the impression that cystic fibrosis mainly involves not being able to touch loved ones for fear of catching germs. But when you get down to the reality of it, cystic fibrosis (CF) is not tragically romantic in the least: it involves much more than needing to stay five feet away from other cystic fibrosis patients.
CF is a devastating recessive genetic disease that results from a mutation in a gene called cystic fibrosis transmembrane conductance regulator (CFTR). This mutation is the most prevalent fatal mutation in Caucasian populations, affecting about 1 in 4,000 people. Despite how common it is, there is no cure for CF (1,4). Those afflicted by CF often experience a buildup of excess mucus that becomes trapped in the lungs and pancreas, which can cause permanent cysts on the lungs, lung infections, lung failure, and even death. Up until the 1970s, the life expectancy of a patient with CF was on the scale of a few months to a few years (2). Though the path of survival is not easy, thanks to many antibiotics, chest physical therapy, and even lung transplants, those with CF can now live to around middle age, on average (3).
Interestingly, CF is not common across all populations, and appears to mainly affect people of European descent. The relatively high, localized prevalence of CF and its persistence in spite of such negative symptoms have led some researchers to hypothesize that the mutation causing CF could actually have a survival advantage in some circumstances. This hypothesis was developed because being a heterozygote (having just one copy, also known as being a carrier) of the CF mutation has no known adverse effects. As a result, if the CF allele could protect people from a dangerous disease like malaria, cholera, or tuberculosis, individuals who are heterozygous for the CF mutation could be protected from that other disease (a heterozygote advantage), while not exhibiting any symptoms of CF. However, until recently, there has been no definitive link between CF and a second disease to support this hypothesis.
A study published in BMC Infectious Diseases in 2017 by Lander Bosch and colleagues sought to test the hypothesis that CF confers a heterozygote advantage. Drawing inspiration from a 2007 study that used historical records to demonstrate a correlation between the occurrence of the CF mutation and tuberculosis outbreaks in Europe in the 1600s (5), Bosch and colleagues wanted to examine current epidemiological data on CF-carrier rates and tuberculosis occurrence, to see if a link between these two diseases could explain the prevalence of CF. Their first task was to find a population of European descent with a high frequency of tuberculosis and readily accessible data on both CF and tuberculosis; Brazil met all these requirements. Next, the researchers collected population census, demographic, and epidemiological data across six states in Brazil. They also collected data on individuals with AIDS, type II diabetes, and smokers, since these are factors that are known to decrease the immunological response to tuberculosis. Statistical analyses were used to compare the frequency of the CFTR mutation with the frequency of tuberculosis in the different regions selected in this study. Consistent with a heterozygote advantage, the authors found that Brazilian states with high CF-carrier rates experienced significantly lower rates of tuberculosis compared to states with low CF-carrier rates, even when controlling for confounding environmental and immunological factors. However, the authors also found that the CFTR mutation was not completely protective against tuberculosis, as there were individuals who possessed the mutation and also had tuberculosis.
Nonetheless, these findings still support the hypothesis that possessing one copy of the CF mutation is beneficial, as the mutation appears to provide an increased resistance to tuberculosis, and might therefore explain why the CF mutation is so common. Bosch and colleagues’ work also raises the question of why possessing a copy of the CFTR mutation does not necessarily completely protect an individual from tuberculosis. Further research on why there may be more or less protection from tuberculosis depending on the individual would be beneficial. This knowledge would not only provide additional information on resistance to tuberculosis, but also may help us gain a more in depth understanding of the CFTR mutation itself, which could also inform the synthesis of future potential treatments for CF. These future research directions are an example of how studying the evolutionary basis of genetic diseases such as CF can point researchers towards interesting questions with direct implications for human health.
I would like to extend a massive thank you to Dr. Daniel Wetzel for his assistance editing this piece, his patience, and for presenting me with this amazing opportunity.
- Bosch L, Bosch B, De Boeck K, Nawrot T, Meyts I, Vanneste D, Le Bourlegat CA, Croda J, da Silva Filho L. 2017. Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory. BMC Infect Dis 17:340.
- Elborn, JS. 2016. Cystic fibrosis. Lancet 388:2519-2531.
- Mackenzie, T., Gifford, A. H., Sabadosa, K. A., Quinton, H. B., Knapp, E. A., Goss, C. H., & Marshall, B. C. (2015). Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: Survival analysis of the cystic fibrosis foundation patient registry. Ann Intern Med. https://doi.org/10.7326/M13-0636
- National Institutes of Health, 2012 Cystic Fibrosis https://ghr.nlm.nih.gov/condition/cystic-fibrosis.
- Poolman EM, Galvani AP. 2007. Evaluating candidate agents of selective pressure for cystic fibrosis. J R Soc Interface 4:91-98.