Thursday, March 11, 2010

More on bugs

We've written before about how it seems that genomewide association studies are finding more and more genes associated with the immune system. And that's for a wide spectrum of conditions, from schizophrenia to macular degeneration to inflammatory bowel disease, and now, Alzheimer's Disease, according to a story in the NYTimes. These genes still explain only a small fraction of risk, but it is certainly starting to look like a trend.

The new hypothesis [about Alzheimer's] got its start late one Friday evening in the summer of 2007 in a laboratory at Harvard Medical School. The lead researcher, Rudolph E. Tanzi, a neurology professor who is also director of the genetics and aging unit at Massachusetts General Hospital, said he had been looking at a list of genes that seemed to be associated with Alzheimer’s disease.
To his surprise, many looked just like genes associated with the so-called innate immune system, a set of proteins the body uses to fight infections. The system is particularly important in the brain, because antibodies cannot get through the blood-brain barrier, the membrane that protects the brain. When the brain is infected, it relies on the innate immune system to protect it.
And, when researchers exposed the protein that constitutes plaque in the brains of many Alzheimer's patients to microbes, it was a fairly efficient killer. While a good fraction of people with dementia are found not to have these plaques upon autopsy, and many people without dementia do have them, the possibility that the innate immune system might fight infection of the brain as well as kill brain cells seems to be real. But it's a complex trait, and like any other complex trait, may well turn out to have more than one cause, one of which may be an innate immune system doing its job too efficiently.

The innate immune system attacks common features of microbes. That's different from the 'adaptive' immune system, which generates a huge array of different antibody molecules by random rearrangement of chromosomal segments (see Mermaid's Tale for some facts about these different systems). Variation in the latter is generated during your life, and inherited variation is not thought to be very important (since the system generates millions of new antibody configurations during your life). Variation in the innate immune system is inherited and works directly, the way genes are usually thought to work: the protein coded by the genetic variant (allele) that you inherit does its job at finding and poking holes in bacteria (or doesn't, depending on its configuration).

Infectious disease can be a strong effect. Whether or not it is systematic and durable enough to relate to natural selection over many generations, it may be that variation in susceptibility can lead to substantially different risk of disease to persons exposed to a given kind of pathogen. If that's the case, then mapping studies -- like GWAS, comparing cases and controls to find parts of the genome that seem to be related to case status -- might be able to detect the stronger risk-effects of genetic variation related to infectious disease. At least, it seems that for a wide variety of diseases a substantial fraction of GWAS 'hits' involve immune or inflammatory genes.

This could be a misleading surmise on our part. The 'immune' system does all sorts of jobs related to molecular recognition, and may involve a larger fraction of the genome than has been thought, so that its involvement in a given disease may not reflect infection, but some other function. Since as we said above these mapping 'hits' only account for a fraction of the case-control contrast, infection can't be the only causal factor.

Secondly, some studies find immune system 'hits' in diseases expected to involve infection, but not for other diseases (like heart disease) that are not. So not everything need be infectious. On the other hand, even something like heart disease risk can in part be due to infection, and instances and mechanisms are known that do that.

So there are interesting things to be found. If infection does turn out to be important, and if we keep over-using antibiotics, we may face a much more serious threat from that direction than from all the claimed 'genetic' risk that so much money is being spent to find by GWAS, biobanks, and other means. If that is the case, hopefully the research effort can be pried from the genetic vested interests in time to address the real problem before it's too late.

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