Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever

Familial Mediterranean fever (FMF) is a recessively inherited disorder pred isposing to renal amyloidosis and associated with mutations in MEFV, a gene encoding a protein of unknown function. Differences in clinical expression have been attributed to MEFV-allelic heterogeneity, with the M694V/M694V g enotype associated with a high prevalence of renal amyloidosis. However, th e variable risk for patients with identical MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, st rongly suggests a role for other genetic and/or environmental factors. To o vercome the well-known difficulties in the identification of modifying gene tic factors, we investigated a relatively homogeneous population sample con sisting of 137 Armenian patients with FMF from 127 independent families liv ing in Armenia. We selected the SAA1, SAA2, and APOE genes-encoding serum a myloid proteins and apolipoprotein E, respectively-as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-reg ression analysis showed that the SAA1 alpha/alpha genotype was associated w ith a sevenfold increased risk for renal amyloidosis, compared with other S AA1 genotypes (odds ratio [OR] 6.9; 95% confidence interval [CI] 2.5-19.0). This association, which was present whatever the MEFV genotype, was extrem ely marked in patients homozygous for M694V (11/11). The risk for male pati ents of developing renal amyloidosis was fourfold higher than that for fema le patients (OR = 4.0; 95% CI = 1.5-10.8). This association, particularly m arked in patients who were not homozygous for M694V (34.0% vs. 11.6%), was independent of SAA1-allelic variations. Polymorphisms in the SAA2 or APOE g ene did nor: appear to influence susceptibility to renal amyloidosis. Overa ll, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian dis order is influenced by at least two MEFV-independent factors of genetic ori gin-SAA1 and sex-that act independently of each other.