Goats, germs, and fever: Are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis?

Mutations in the MEFV gene are highly prevalent in the Middle East and Mediterranean basin, with carrier rates of up to 1:3 in some populations. More than 50 mutations in the MEFV gene have been described. The high prevalence, multiple mutations, and geographic localization to the Middle East suggest a positive selection advantage for the abnormal gene operating in this area over the last several thousand years. To date, no satisfactory explanation of this phenomenon has been made. Rather, many harmful effects of these mutations have been described. MEFV gene mutations cause familial Mediterranean fever in homozygotes, a disease associated with recurrent febrile inflammatory episodes, and death from renal failure and amyloidosis. Heterozygotes with MEFV mutations are predisposed to premature coronary disease, and rheumatologic conditions such as Behcet's disease. MEFV mutations do not appear to protect against tuberculosis. Brucellosis is still highly endemic in the Middle East because of the traditional reliance for meat and dairy production on goats and sheep, the major vectors for this zoonosis. Brucellosis causes a prolonged febrile illness lasting for months and even years, and it may have exacted a major toll among Bronze Age peasant populations in the Middle East. The gene product for MEFV, pyrin, normally inhibits interleukin-1 beta production. Mutations in MEN result in a pro-inflammatory state, with a Th1 polarization and high levels of interferon-gamma. This may actually be protective against intracellular pathogens such as brucellosis. The possible heterozygote advantage of MEFV mutations against brucellosis may therefore be a balanced polymorphism, analogous to the protective effect against malaria that maintains high levels of sickle cell trait in sub-Saharan Africa. (c) 2006 Elsevier Ltd. All rights reserved.