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Why is cystic fibrosis (CF) one of the most common genetic diseases? Could heterozygous carriers have a selective advantage?
The infection that CF carriers may be protected against is absolutely astounding.
#medthread #medtwitter #tweetorial
Why is cystic fibrosis (CF) one of the most common genetic diseases? Could heterozygous carriers have a selective advantage?
The infection that CF carriers may be protected against is absolutely astounding.
#medthread #medtwitter #tweetorial
2/
Three types of supporting evidence are required to determine whether CF carriers plausibly have a selective advantage against an infectious pathogen:
💥 Historical/geographical
💥 Clinical/population
💥 Molecular
Let's examine these one by one.
ncbi.nlm.nih.gov/pmc/articles/P…
Three types of supporting evidence are required to determine whether CF carriers plausibly have a selective advantage against an infectious pathogen:
💥 Historical/geographical
💥 Clinical/population
💥 Molecular
Let's examine these one by one.
ncbi.nlm.nih.gov/pmc/articles/P…
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💥 Historical/geographical
The first inkling that CF carriers may have a selective advantage came from observations that patients w/ cystic fibrosis rarely get tuberculosis (TB).
TB infection is so rare in CF patients that it's case-reportable.
ncbi.nlm.nih.gov/pubmed/26110137
💥 Historical/geographical
The first inkling that CF carriers may have a selective advantage came from observations that patients w/ cystic fibrosis rarely get tuberculosis (TB).
TB infection is so rare in CF patients that it's case-reportable.
ncbi.nlm.nih.gov/pubmed/26110137
4/
Like sickle cell carriers who are protected from malaria, is there historical/geographical evidence for CF carrier protection from TB?
TB infection rates in Europe increased dramatically during a pandemic known as the White Plague (1600-1900), where TB caused 20% of deaths.
Like sickle cell carriers who are protected from malaria, is there historical/geographical evidence for CF carrier protection from TB?
TB infection rates in Europe increased dramatically during a pandemic known as the White Plague (1600-1900), where TB caused 20% of deaths.
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European pandemic TB mortality rates accurately predicted modern Caucasian CF carrier rates (1:30), if a selective advantage for CF carriers was assumed.
Translation: Protection from TB seems to explain why Caucasian CF carriers are so common.
ncbi.nlm.nih.gov/pmc/articles/P…
European pandemic TB mortality rates accurately predicted modern Caucasian CF carrier rates (1:30), if a selective advantage for CF carriers was assumed.
Translation: Protection from TB seems to explain why Caucasian CF carriers are so common.
ncbi.nlm.nih.gov/pmc/articles/P…
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💥 Incredibly, there is clinical evidence for this theory:
A Brazilian epidemiology study found the incidence of TB inversely correlated w/ rates of CF carriers (they studied delta F508, the most common CF mutation)
🤯 more CF carriers = less TB
ncbi.nlm.nih.gov/pmc/articles/P…
💥 Incredibly, there is clinical evidence for this theory:
A Brazilian epidemiology study found the incidence of TB inversely correlated w/ rates of CF carriers (they studied delta F508, the most common CF mutation)
🤯 more CF carriers = less TB
ncbi.nlm.nih.gov/pmc/articles/P…
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💥 Assuming that CF carriers are protected from TB, what could the molecular mechanism be?
No one knows for sure but let's break down a leading theory...
Recall that TB has a complex cell wall, including the need to incorporate glycolipids.
researchgate.net/figure/The-cel…
💥 Assuming that CF carriers are protected from TB, what could the molecular mechanism be?
No one knows for sure but let's break down a leading theory...
Recall that TB has a complex cell wall, including the need to incorporate glycolipids.
researchgate.net/figure/The-cel…
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These glycolipids help protect the TB bacterium from attack by the host, and to do so they have to be sulfated.
When taken up by macrophages, TB's sulfated glycolipids prevent phagolysosomes from fusing, protecting the bacterium from destruction.
ncbi.nlm.nih.gov/pmc/articles/P…
These glycolipids help protect the TB bacterium from attack by the host, and to do so they have to be sulfated.
When taken up by macrophages, TB's sulfated glycolipids prevent phagolysosomes from fusing, protecting the bacterium from destruction.
ncbi.nlm.nih.gov/pmc/articles/P…
9/
TB can't create its own sulfate groups as it lacks an enzyme called arylsulfatase B (ARSB). The bacterium relies on the human host to use its own ARSB to free up sulfate.
TB would have a hard time infecting humans if deprived of sulfate.
ncbi.nlm.nih.gov/pubmed/12144918
TB can't create its own sulfate groups as it lacks an enzyme called arylsulfatase B (ARSB). The bacterium relies on the human host to use its own ARSB to free up sulfate.
TB would have a hard time infecting humans if deprived of sulfate.
ncbi.nlm.nih.gov/pubmed/12144918
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It turns out that patients w/ cystic fibrosis have decreased levels of activity of the arylsulfatase B enzyme, probably because higher chloride levels disrupt trafficking of the protein inside cells.
ncbi.nlm.nih.gov/pubmed/22550062
It turns out that patients w/ cystic fibrosis have decreased levels of activity of the arylsulfatase B enzyme, probably because higher chloride levels disrupt trafficking of the protein inside cells.
ncbi.nlm.nih.gov/pubmed/22550062
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Although enzyme activity in CF carriers has not been studied, the theory for why they may be protected from TB is:
⬇️ arylsulfatase B = ⬇️ free sulfate = ⬇️ TB
ncbi.nlm.nih.gov/pubmed/12796199
Although enzyme activity in CF carriers has not been studied, the theory for why they may be protected from TB is:
⬇️ arylsulfatase B = ⬇️ free sulfate = ⬇️ TB
ncbi.nlm.nih.gov/pubmed/12796199
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To summarize:
💡 The frequency of CF carriers implies a selective advantage
💡 Cystic fibrosis patients almost never get TB
💡 There is historical/population evidence suggesting CF carriers are protected from TB
💡 ⬇️ arylsulfatase B activity may explain this protection
To summarize:
💡 The frequency of CF carriers implies a selective advantage
💡 Cystic fibrosis patients almost never get TB
💡 There is historical/population evidence suggesting CF carriers are protected from TB
💡 ⬇️ arylsulfatase B activity may explain this protection
Addendum:
A number of people have asked about whether CF carriers are protected against cholera.
It turns out there‘a evidence against protection from cholera as CF heterozygotes secrete as much chloride in response to cholera toxin as wild types.
ncbi.nlm.nih.gov/pubmed/11055897
A number of people have asked about whether CF carriers are protected against cholera.
It turns out there‘a evidence against protection from cholera as CF heterozygotes secrete as much chloride in response to cholera toxin as wild types.
ncbi.nlm.nih.gov/pubmed/11055897
