Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148

Familial Mediterranean fever (FMF) is caused by more than 25 mutations in t he gene MEFV, which encodes pyrin (marenostrin), a protein implicated in th e regulation of neutrophil activity. Pyrin Q148, is one of the five most co mmon variants in populations in which FMF typically occurs. Our identificat ion of the pyrin Q148 allele in several patients from ethnic groups in whic h FMF is not classically recognized who had longstanding fevers or AA amylo idosis prompted us to study the prevalence of pyrin Q148 in healthy British , Indian and Chinese subjects. The gene frequency was also sought in 50 Bri tish Caucasian patients with inflammatory arthritis, 25 of whom had AA amyl oidosis, five Punjabi Indians with AA amyloidosis complicating inflammatory arthritis, and seven British Caucasian patients with uncharacterized longs tanding fever syndromes. The allele frequency for pyrin Q148 was 21%, 15% a nd 0%, respectively, among Punjabi Indian, Chinese and Caucasian British co ntrols, and was significantly increased among the patients with AA amyloido sis and the patients with obscure fever syndromes (p <0.01). Pyrin Q148 is a polymorphism and occurs widely in global terms, and, although it may caus e FMF when associated with certain other MEFV mutations, homozygosity for Q 148 alone must usually be insufficient to produce FMF in the populations st udied. The association of pyrin Q148 with AA amyloidosis and with obscure c hronic inflammatory diseases suggests the variant may augment inflammation non-specifically, which might have been beneficial during evolution, but co uld potentially exacerbate many chronic inflammatory disorders.