Identification ofMEFV‐Independent Modifying Genetic Factors for Familial Mediterranean Fever

Abstract

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 SAA1alpha/alpha 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.

Relative transcriptional activities ofSAA1promoters polymorphic at position −13(T/C): Potential association between increased transcription and amyloidosis

“…It is clear that the genotypes at the SAA1 locus are associated with a susceptibility to develop AA- amyloidosis, although it appears that the susceptible alleles differ amongst different ethnic populations [9][10][11][12][13][14][15][16][17]. So far, there has been no reported study indicating the mechanism whereby the allelic variants at the SAA1 locus influence amyloidogenicity.…”

“…While an MEFV missense mutation, M694V, is associated with a severe course of FMF and developing AA-amyloidosis [2][3][4][5][6][7][8], the risk associated with the SAA1 gene and developing AAamyloidosis is still controversial. Although homozygosity for SAA1.1 is reported to be a risk factor for the development of AA-amyloidosis in patients with FMF [9][10][11] and in Caucasians with RA [12,13], this is not the case in the Japanese RA population. The SAA1.3 allele and not the SAA1.1 allele was closely associated with AA-amyloidosis in Japanese RA patients [14][15][16][17], with the SAA1.1 allele frequency being significantly less in Japanese AA-amyloidosis patients than in controls.…”

Genetic Risk Factors of Amyloidogenesis in Familial Mediterranean Fever

“…But no relation between SAA1 and amyloidosis could be demonstrated. Cazeneuve et al [16] reported a 7-fold increased risk for amyloidosis in the SAA1 α/α genotype by detecting the relation between the SAA1 and SAA2 genotypes in FMF patients. Yılmaz et al [18] evaluated the SAA and TNFα gene polymorphisms in 173 Turkish patients with amyloidosis.…”

“…Catabolism of overproduced SAA protein is disturbed and it is deposited in the form of protease-resistant fibrils mainly in phagocytic cells in tissues. In SAA1 gene polymorphism especially the SAA1 α/α genotype has been found to facilitate the development of amyloidosis in FMF patients [16,17,18,19,20]. …”

Population screening for single genes that codetermine common diseases in adulthood had limited effects

“…This, despite of increased awareness, and the availability of DNA testing. In recent years several studies indicate that genotypephenotype relationships for FMF are unpredictable [42,43].…”