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Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever
C Cazeneuve1, H Ajrapetyan, S Papin
1Service de Biochimie et de Génétique Moléculaire and Institut National de la Santé et de la Recherche Médicale (Unité 468), H opital Henri-Mondor, 94010 Créteil, France.
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.
Insights
Familial Mediterranean Fever (FMF) risk for renal amyloidosis is influenced by SAA1 genotype and patient sex, independent of MEFV mutations. These factors increase susceptibility to this severe complication.
Area of Science:
- Genetics
- Immunology
- Nephrology
Background:
- Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disorder.
- FMF predisposes patients to renal amyloidosis, a severe complication.
- The MEFV gene mutations explain FMF but not all clinical variations, suggesting other factors are involved.
Purpose of the Study:
- To identify genetic and non-genetic factors modifying renal amyloidosis risk in FMF patients.
- To investigate the role of SAA1, SAA2, and APOE genes and sex as potential modifiers.
Main Methods:
- Study population: 137 Armenian FMF patients from 127 families.
- Statistical analysis: Stepwise logistic regression.
- Candidate genes: SAA1, SAA2, APOE, and patient sex.
Main Results:
- The SAA1alpha/alpha genotype significantly increased renal amyloidosis risk (OR=6.9).
- Male patients had a fourfold higher risk of developing renal amyloidosis (OR=4.0).
- SAA1 and sex acted independently of MEFV genotype and each other.
Conclusions:
- Renal amyloidosis susceptibility in FMF is influenced by MEFV-independent factors.
- SAA1 genotype and male sex are significant risk factors for renal amyloidosis in FMF.
- These findings offer new insights into FMF pathophysiology and amyloidosis development.