Résumé
Familial Mediterranean fever (FMF) is a recessively inherited disorder predisposing 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 genotype associated with a high prevalence of renal amyloidosis. However, the variable risk for patients with identical
MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, strongly suggests a role for other genetic and/or environmental factors. To overcome the well-known difficulties in the identification of modifying genetic factors, we investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. We selected the
SAA1, SAA2, and
APOE genes—encoding serum amyloid proteins and apolipoprotein E, respectively—as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-regression analysis showed that the
SAA1α/α genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other
SAA1 genotypes (odds ratio [OR] 6.9; 95% confidence interval [CI] 2.5–19.0). This association, which was present whatever the
MEFV genotype, was extremely marked in patients homozygous for M694V (11/11). The risk for male patients of developing renal amyloidosis was fourfold higher than that for female patients (
OR=4.0; 95%
CI=1.5–10.8). This association, particularly marked 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 gene did not appear to influence susceptibility to renal amyloidosis. Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two
MEFV-independent factors of genetic origin—
SAA1 and sex—that act independently of each other.