On the History and Prevalence of Cystic Fibrosis

Cystic fibrosis (CF) has been shortening lives for quite some time now. The earliest references date back to the Middle Ages and show that salty skin (typical for CF patients) has been recognized as a symptom of a disease associated with mortality. A child that tasted “salty” when kissed was considered hexed and predicted to die soon. European medieval folklore warned, “Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon will die.” Typically, for this era, this incurable deadly disease was attributed to witchcraft¹.

Near the end of the 16^th century, an autopsy of a dead “bewitched” child noted significant damage to the pancreas¹. The first description of the disease in medical literature came from 1938, where Dr. Andersen called it “cystic fibrosis of the pancreas” based on the autopsy findings of children who had died of malnutrition². This is how the disease got its name. Several years later, during a heatwave, it was noted by Dr. di Sant' Agnese that children with CF had abnormally high concentrations of salt in their sweat³. Based on the ever-present mucus in patients with CF, many physicians also referred to the disease as mucoviscidosis. While the way of inheriting CF suggested recessive genetic disease, it wasn't until 1989 that the responsible gene was discovered, which enabled significant medical progress in treating CF. Nowadays many people with CF can benefit from personalized treatment and hopefully, genetic therapies will enable this progress to continue on further.

What remains intriguing is the high prevalence of CF mutations in the population. Moreover, there is a huge gap between the overall frequency of the most common mutation, F508del, and all the other mutations – while F508del accounts for about two-thirds of all CF-causing mutations, only four other mutations have overall frequencies more than one percent⁴. The F508del mutation is simply far too frequent. The question is, what made this mutation so common? Does it have any advantage to carry this mutation?

The high frequency of CF carriers, most of them with F508del, suggests some possible advantage of CF carriers over “healthy” individuals. The advantage can be in increased fertility of the carriers, or in surviving some serious and prevalent disease. Sickle cell anemia is a great example of the latter, as carriers of that mutation have an advantage in surviving malaria⁵. Analysis of fertility showed no differences between CF carriers and “healthy” individuals, which tilts the scales towards an advantage against some disease⁶. CF carriers were thought to be more resistant to diarrhea-causing toxins (toxins from Vibrio cholerae and Escherichia coli), however, it was later disputed⁷. F508del as protection against typhoid fever also lacks evidence⁸. Besides, these diseases are more common in tropical regions, which is in stark contrast to the distribution of F508del. Probably the most substantial theory so far is the potential advantage of F508del against tuberculosis⁹.

To come closer to understanding the why, it is best to start with determining when and where F508del came from. Studies of ancient DNA from an Iron Age burial site in Central Europe uncovered the presence of the F508del mutation in 3 out of 32 individuals buried there¹⁰. These findings indicate that F508del has been present for more than 2300 years. Alas, not many human remains older than that are readily available for testing. However, to understand the past, we can look at the state of CFTR mutations in people who are currently living. Using specific DNA sequences called microsatellites (DNA repeat sequences that mutate faster than other parts of DNA) located near and within the CFTR gene, it is possible to trace the origin and evolution of different CF mutations.

The previous attempts to estimate the age of F508del yielded contradictory results, ranging from more than 40,000 years to 3000 years⁴. Newest research estimated the origin of F508del about 4600-4725 years ago in the northwestern European population, from where it spread to the central and southeastern populations, the latter only about 1000 years ago¹⁰. This spread of F508del corresponds with the time period and direction of Bronze Age human activities. These Europeans migrated extensively and apparently were not exposed to epidemics, so unlike the case of sickle cell anemia, these findings do not support germ-related selection advantage of F508del. Hopefully further archeological and DNA studies of Bronze Age people will shed light on the widespread presence of F508del¹⁰.

References

• ¹ - P. M. Quinton, “Physiological basis of cystic fibrosis: A historical perspective,” Physiological Reviews, vol. 79, no. 1 SUPPL. 1. American Physiological Society, 1999.
• ² - D. H. Andersen, “CYSTIC FIBROSIS OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASE,” Am. J. Dis. Child., vol. 56, no. 2, p. 344, Aug. 1938.
• ³ - P. A. DI Sant’agnese, R. C. Darling, G. A. Perera, and E. Shea, “Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas; clinical significance and relationship to the disease,” Pediatrics, vol. 12, no. 5, pp. 549–563, Nov. 1953.
• ⁴ - E. Mateu, F. Calafell, M. D. Ramos, T. Casals, and J. Bertranpetit, “Can a place of origin of the main cystic fibrosis mutations be identified?,” Am. J. Hum. Genet., vol. 70, no. 1, pp. 257–264, 2002.
• ⁵ - M. Aidoo et al., “Protective effects of the sickle cell gene against malaria morbidity and mortality.,” Lancet, vol. 359, no. 9314, pp. 1311–1312, 2002.
• ⁶ - L. B. Jorde and G. M. Lathrop, “A test of the heterozygote-advantage hypothesis in cystic fibrosis carriers,” Am. J. Hum. Genet., vol. 42, no. 6, pp. 808–815, 1988.
• ⁷ - C. Högenauer et al., “Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion.,” Am. J. Hum. Genet., vol. 67, no. 6, pp. 1422–7, Dec. 2000.
• ⁸ - E. van de Vosse et al., “Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR).,” Hum. Genet., vol. 118, no. 1, pp. 138–40, Oct. 2005.
• ⁹ - E. M. Poolman and A. P. Galvani, “Evaluating candidate agents of selective pressure for cystic fibrosis,” J. R. Soc. Interface, vol. 4, no. 12, pp. 91–98, Feb. 2007.
• ¹⁰ - P. Farrell et al., “Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis,” Eur. J. Hum. Genet., vol. 26, no. 12, pp. 1832–1839, Dec. 2018.