This multidisciplinary, multiscalar study in Brazil is, to our knowledge, the first to address the hitherto theoretical link between CF carriership and TB incidence on a contemporary patient dataset. We found a significant, inverse correlation between both, that remained valid after thorough correction for potential environmental and immunological confounders.
Our approach is innovative as it highlights 3 additional aspects to this hypothesis: 1. It extends the idea that human genetics are an important factor in infectious diseases; 2. It studies a possible evolutionary advantage in a representative contemporary environment; 3. It shows how health geography can contribute substantially to elucidating a medical hypothesis.
First, the human genetics of infectious diseases paradigm, the idea that a genetic defect can predispose to a specific infectious pathogen, has revolutionized modern medicine [22]. Increasingly, mutations and new genes are being identified that render the host susceptible to a specific pathogen [23]. Several genetic defects in the defence against TB have been identified [24]. This allows understanding why, whilst most TB-exposed individuals only have latent disease, particular patients develop fulminant TB disease (‘low disease burden’, ‘high susceptibility’). Our research explores the same idea of a genetic determinant in infectious disease. However, it changes the question to why, despite having a high chance of developing disease, some people have relative protection against the disease (‘high disease burden’, ‘low susceptibility’). Important examples of already elaborated ‘resistance genetics’ include sickle cell trait in survival advantage against malaria [25] and the CCR5-delta32 mutation in HIV resistance [26].
Yet, the field of ‘resistance genetics’ is still highly unexplored. Brazil figures among the WHO listed 22 ‘high burden’ countries for TB. At a municipality level, we showed that the group of CF carriers did not have a lower TB burden than other Brazilians [27]. Notwithstanding this high burden, we found an inverse correlation between CF carriership and TB incidence, suggesting a lower susceptibility of CF carriers to TB infection.
Second, in both malaria and HIV, the geographic spread of the ‘resistance allele’ led to the unravelling of the link with its respective infectious disease. Also for our research, the choice of an appropriate place has proven crucial. Brazil is the only country worldwide that combines high TB incidence with the European TB strain and a high CF carriership background, making statistical analyses possible. We were able to study this large cohort thanks to access to the detailed Brazilian registry for TB and CF. In this way evolutionary genetics can be studied in a representative contemporary environment.
Third, this study emphasizes the importance of a multidisciplinary approach to evolutionary genetics. For many years, the question why CF is so frequent amongst Caucasians has been posed in medical literature, yet no in-depth study has been undertaken to more definitively answer this question. We show that Brazil’s geographical, socio-economic and demographic diversity make it possible to approach the role and impact of CFTR mutations on TB infection, as well as of various external determinants. This complexity could only be unravelled by means of spatial analysis on medical registry data.
Now, the question goes back to the biomedical bench, as only by cell biological research it will be possible to elucidate and validate the molecular mechanisms behind the found correlation. This biomedical validation is essential to sustain this first preliminary evidence.
The multidisciplinary population-based approach of our study covering 116 million Brazilian inhabitants is a major strength, yet this method also implies several limitations. First, the minimum CFTR mutation carriership rates for the municipalities are only a proxy of the real carriership frequency. As registry data were anonymized, it cannot be excluded that siblings are counted as individual patients, introducing an overestimation in the number of carriers. Most probably, however, our data are an underestimation of the CF carrier rate, as siblings with a CFTR mutation have not been taken into account, CF carriers not directly related to registered patients could not be identified, and not all CF cases are diagnosed correctly. Brazil has recently initiated systematic newborn screening for CF. As such, many CF cases that would go unnoticed in countries without screening, are now picked up. The frequency of CF disease has been shown to be linked with carriership rate [28].
Next, the structure of both SINAN-TB and REBRAFC registries limited the choice of aerial units that could be chosen for the analyses. The municipality level was the most detailed scale of research possible. Nevertheless, this scale remains susceptible to ecological fallacy. To address this limitation, a case-control study comparing the CF carrier rate of individual Brazilian patients with proven TB to age-, sex- and socio-economically matched healthy individuals from the same municipality could be envisaged. Future research could focus on the genetic background of individual patients with TB.
Lastly, we could not study the link between carrying CF and nontuberculous mycobacterial (NTMs) infection, as systematic municipality data on NTMs are lacking. Primary immune deficiency (PID) patients with Mendelian Susceptibility to Mycobacterial Disease develop severe Mtb and NTM infections [29], and patients with CF have a high susceptibility to infections with NTMs [30]. It can therefore feel counterintuitive that carrying one CFTR mutation would not result in an increased but rather a reduced Mtb infection rate. Yet Mtb and NTMs also differ importantly: they constitute a distinct group within the Mycobacteria family and have separate host traits, clinical features [31], and drug resistance patterns [32]. Recent findings in PID support that the immunological response to NTMs might be different from that to Mtb [33].
Notwithstanding these limitations, we found indications for the relative protective role of carrying a single CF mutation against infections with Mtb on two scales on the Brazilian territory.
The possibility that CF carriership has (had) an evolutionary advantage has been raised before. Candidate agents of selective pressure for CF include cholera [34], typhoid fever [35] and tuberculosis. Poolman and Galvani computed that only the European tuberculosis pandemic in the early 1600s can have provided sufficient selective pressure to explain the modern CF incidence [7]. On the other hand, it is also known that a mutation in CFTR cannot be fully protective against Mtb infection, as cases of patients with CF and TB have been reported [36].
Never before however, a study has addressed this theoretical hypothesis with patient data.
This observation is relevant, as a rationale for the high CF incidence in Euro-descendants could now be provided. Equally, once a potential human protection mechanism against Mtb infection can be uncovered, this opens up opportunities for the development of new treatment strategies against the disease and implies a vital step towards eradicating TB worldwide.
