Familial Mediterranean fever

FMF is a recessive hereditary disorder caused by mutations in MEFV, the gene for the protein pyrin. Pyrin, produced in white blood cells,  inhibits inflammation, and the FMF mutations unleash inflammation to varying degrees.

The disease manifests in painful inflammatory attacks in various parts of they body, usually accompanied by fever.  Most patients have abdominal attacks and  joint attacks, and chest attacks are also common.

Amyloidosis leading to kidney failure used to be common, before colchicine treatment was introduced.

It’s found in populations that originated in the eastern Mediterranean: Armenians, Sephardic Jews, North African Jews, Arabs, and Turks.   Carrier frequencies can be as high as as 1 in 5  in Turks, Arabs and Armenians.  Ashkenazi Jews have a fairly high carrier frequency as well, but  they seem to have milder mutations that are less likely to cause serious disease.

Obviously mutations that inactivated pyrin to some degree had a significant selective advantage in these populations.  There’s no other way for MEFV mutations to have become regionally common, way above mutation-selection equilibrium – particularly when they’re bad for homozygotes.

The question is, what was the advantage?  Sure looks as if MEFV mutations gave protection against some infectious disease – one that significantly dinged fitness in the Middle East.  The usual suspect is malaria, which has generated most of the common expensive genetic defenses 0 but it can’t be malaria.  If it were, we’d see some version of FMF in Southeast Asia, or Sub-Saharan Africa, or New Guinea, and we don’t.

I’m just spitballing , running it up the flagpole to see who salutes, but I wonder if it wasn’t leishmaniasis getting out of control among early agriculturalists.


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7 Responses to Familial Mediterranean fever

  1. Here is a question only slightly related to the post. I keep reading references to things like a part of an ancient grave yard in Egypt being all blondes and another part all redheads. Or that various famous members of ancient greek society were red heads or blonds. But you go through that part of the world today and very very rarely does any local have anything but dark hair. I am guessing that people from this part of the world became considerably darker since classical times because genes for darker hair and skin hitch hiked along with genes that provided protection from equatorial diseases which we both know have become far more prevalent since classical times.

    But I haven’t read that anywhere, it just seems to make sense to me. What do you think?

  2. Patrick Boyle says:

    Speaking of Colchicine, it’s been in the news lately because of its price hike. The FDA seems to have managed to have forced up the price of colchicine by 50 times. It went from a dime per pill to five dollars overnight. Their rules prohibit any other drug manufacturer from making Colchicine so there can be no price competition.

    Colchicine is one of the oldest effective drugs known – maybe the oldest. It was used by the Egyptians. It has been used for gout for thousands of years. It was always an inexpensive drug until a few years ago when the FDA got involved.

    When the TV series ‘House’ was first out I was working on a data base contract at a hospital. All the doctors were talking about the show. I began watching too. It was a medical ‘who done it ?’. But the mysteries were quiet obscure. They were not easy to figure out at all. I figured out the responsible mystery disease only twice. They used a colchicine overdose in two episodes and I spotted it both times. Since I’m not a doctor I take this as evidence that colchicine is well understood.

    The FDA has facilitated a fraud on the public.

  3. sprfls says:

    I never heard of FMF before my wife and I did 23andme (pre FDA health ban, the bastards). Turns out she is a carrier. (–>100% Ashkenazi, despite her family’s claims of distant alternate Jewish ancestry because they are “swarthy”). It looks like a lot of the auto-inflammatory diseases common in Jews are some kind of responses to early urbanism and agriculture.

    Anyways, here’s a bit of what 23andMe has to say about FMF:

    “Many mutations in the MEFV gene associated with FMF have been documented so far. 23andMe reports data for 10 mutations that account for the majority of mutations found in people with Turkish, Arab, Sephardic Jewish and Armenian ancestry. The prevalence of FMF varies in these populations. One out of every 1,000 Turks is thought to have FMF. In Arab populations, the prevalence has been estimated to be one in 2,600. One out every 250 to 1,000 Sephardic Jews is thought to be affected, and in Armenians the estimated prevalence is one out of every 500 people.

    Three of the mutations tested for by 23andMe—E148Q, P369S and K695R—may not actually cause FMF. Recent research suggests that they may instead be involved in modulating inflammatory responses to environmental agents. Therefore, these mutations are not included in 23andMe’s determination of whether or not you are likely to have FMF. However, E148Q, P369S and K695R are included in the table in the technical report so that you can share a more complete picture of your genetics with your health care professional.”

  4. John Hostetler says:

    Greg, do you have particular reasons to suspect Leishmaniasis other than the important geographical fit? According to Wiki, it’s the visceral form that’s the most dangerous, and that’s more distributed in the Indian subcontinent than ME/N Africa. If your idea is correct, maybe the visceral form was more common in the ME before the FMF gene spread.

    It’s interesting that pyrin is said to be produced in neutrophils, eosinophils and monocytes. The fact that basophils aren’t on the list is probably irrelevant, but it seems lymphocytes produce little or no pyrin, which in turn suggests it’s not that important in cell-mediated immune functions. It would be good to know whether eosinophils are particularly rich in it – that would suggest a particular role for pyrin in infection by eukaryotic parasites, supporting your idea.

  5. jeffhsu3 says:

    In addition to the coding variants in the MEFV gene there are common variants affecting gene expression of MEFV in whole blood: http://www.gtexportal.org/home/gene/MEFV.

  6. RCB says:

    I don’t know anything about this, but… the argument that “we don’t see it in other malarial locations, therefore it’s not for malaria” doesn’t seem very strong to me. It could be one of your “Stooge effects” operating: other adaptations for malaria already existed elsewhere, so FMF had little/no selective advantage. I don’t know any microbiological details that suggest malaria, though.

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