Identification of MEFV-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.

The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

“…This study was conducted on a large cohort of FMF patients, in whom both FMF alleles have been characterized. It strengthens the observations made by Cazeneuve et al (20) implicating both male sex and the SAA1␣/␣ genotype as modifiers associated with increased susceptibility to renal amyloidosis. Our study shows that genotypes at both the MEFV and the SAA1 loci additively and independently contribute to the development of amyloidosis (OR 4.27, 95% CI 2.01-9.07 and OR 2.99, 95% CI 1.47-6.09, respectively).…”

“…Susceptibility to amyloidosis has been related to sex and genotypes at the MEFV and the SAA1 loci (20,30). It is higher in men, in individuals homozygous for either the M694V mutation or the complex E148Q-V726A allele (8)(9)(10)(11)(12)(13)(14)30), and in individuals homozygous for the SAA1␣ isoform (20). Polymorphisms at the MICA (major histocompatibility complex class I chain-related gene A) gene were also found to play a role as modifiers in FMF (31).…”

“…They asserted that in Caucasians, contrary to the findings in Japanese subjects in whom the 13T allele is linked to the ␥ allele, the 13T allele was more frequently associated with the ␣ allele, allowing for the discrepant association of either the SAA1␣ or SAA1␥ alleles with AA amyloidosis in RA patients of either Japanese or Caucasian descent, and implicating the 13T allele, rather than the ␥ or ␣ alleles, as a marker of AA amyloidosis (26). Cazeneuve et al (20) investigated relationships between genotypes at the SAA1 and SAA2 loci in patients with FMF and found a significant association between the SAA1␣/␣ genotype and the risk for amyloidosis.…”

“…Of these, polymorphisms at the SAA1 (serum amyloid A1) locus, or rather the SAA1␣/␣ genotype, were found to influence susceptibility to renal amyloidosis in patients with FMF (20).…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…In both the Israelis and Armenians, male sex as well as the SAA1.1 allele are associated with a higher frequency of renal amyloidosis. 87,88 A similar analysis in patients with the HIDS, who rarely have amyloid, did not show any difference in the distribution of SAA alleles compared to population controls despite the fact that they had very high SAA levels. No studies were carried out to determine the distribution of the À13 T/C alleles in the SAA promoter.…”