Septic death and human ACID genetics?

April 5, 2005

It is highly evident that genes contribute to ACID predisposition.

Assuming for the moment that ACIDs are simply chronic intracellular

infections, there is the possibility that their existence is partly

conditioned by selection against death due to septic shock, ie, death

due to a massive acute infection, which has been extremely common in

the human past.

Alleles contributing to ACID might be preserved in the gene pool at

low frequency - rather than being completely eliminated - because

their bearers are resistant to dying from severe inflammatory response

to gross acute infection.

Consider the function-impairing mutations of the monocyte

intracellular bacteria-sensing receptor protein NOD2, which are

associated with Crohn's disease. As I recall, humans heterozygous for

such a mutant allele have a ~2.5-fold increased risk of developing

Crohns, while homozygous humans have a ~30-fold increased risk (still,

the majority of people with Crohns have no such mutation, and most

people with the mutations dont have Crohns). When NOD2 knockout mice

were produced recently, it was found that they 'enjoyed' a

" substantial protective effect in systemic endotoxin challenge. "

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Similarly, " caspase-1 knockout mice exhibit marked resistance to

endotoxin-induced sepsis. " Deletion of the mouse caspase-1 gene does

not model any known human mutation like with NOD2, but it does show

that caspase-1 is involved in the injury/death of septic shock. It

might also play a role in immunity, especially against itnracellular

pathogens.

Finally, I read somehwere that a certain human TLR4 variation confered

increased suceptibility to septic shock death, but decreased

suceptibility to arteriosclerosis, which may be an ACID.

This idea does nothing to explain trends this centruy, such as the

fact that inflammatory bowel disease, for instance, has evidently

increased in incidence substantially in the US since 1940.

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