Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. METHODS: Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). RESULTS: Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. CONCLUSION: Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.

Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population.

OBJECTIVE: Familial Mediterranean Fever (FMF) is an autoinflammatory periodic disorder characterized by febrile and painful attacks due to inflammation involving the serosal membranes. The gene implicated in this disorder, MEFV, has been cloned and mutations in its coding regions have been identified. We aimed at identifying the frequency of MEFV mutations and carrier frequency in a mixed Arabic population. METHODS: We identified 29 probands from 29 unrelated sibships segregating the disorder and representing the affected individual cohort. We screened 200 anonymous deoxyribonucleic acid (DNA) samples, representing a healthy adult cohort, for the mutations found to be common in the affected individual cohort. We also, screened anonymous DNA samples from 4 Arabic countries, namely, Egypt (231), Syria (225), Iraq (176) and the Kingdom of Saudi Arabia (107) thus enlarging our healthy adult cohort. The study was carried out between 1999 and 2002 at Jordan University of Science and Technology, Irbid and the University of Jordan, Amman, Jordan. RESULTS: Out of the 58 alleles of the 29 probands, only 31 mutations were identified and M694V and V726A are the most common. The mutation E148Q was the most common among the healthy adult cohort, but was not present in affected individuals. The collective mutant allele frequency "q" was 0.101. The expected carrier rate was 18.1% (one in 5.5) while the observed carrier rate was 18.4% (one in 5.4). CONCLUSION: E148Q has reduced penetrance and thus, a proportion of the individuals genetically affected with FMF remain asymptomatic. M694I and M680I are more prevalent in the affected individuals cohort, which points to their higher penetrance. The overall carrier rate is one in 5, but the selective heterozygote advantage could not be demonstrated in this study due to the relatively small sample size.