MEFV heterogeneity in Turkish Familial Mediterranean Fever patients

Turkey is one of the few countries in the world where Familial Mediterranean Fever (FMF), an autoinflammatory disease caused by mutations in MEFV, the gene encoding pyrin, is not rare. Many interesting studies regarding the genetics of Familial Mediterranean Fever in Turkey have been already published. Despite that different MEFV genetic profiles have been revealed for Turkish FMF patients, deriving from different regions of Turkey, a systematic population genetics analysis has not been carried out yet. The present study aims to investigate the population genetics of MEFV in Turkish FMF patients so as to additionally facilitate the clinical interpretation of individualized genetic data. All relevant studies have been recruited by searching PubMed with the terms "MEFV", "FMF", and "Turkey". Seven of them, including 3,061 FMF patients, contained all necessary data concerning allelic and genotypic frequencies of the 4 commonest MEFV mutations in Turkey (M694V, V726A, M680I, E148Q). From all 6,122 MEFV alleles analyzed, the M694V mutation was recognized in 15.6-52.2% (mean 29.3%), the V726A in 1.5-9.7% (mean 4.8%), the M680I in 1.5-15.5% (mean 7.6%), and the E148Q in 3.2-13.9% (mean 5.5%). Unidentified mutations ranged from 0-42.9% (mean 16.8%). No mutations were found in 0-54.5% (mean 36.0%) of the patients. The allelic and genotypic frequencies of the most frequent mutation (M694V) showed aberration of the Hardy-Weinberg law for all 7 populations studied. By application of the Arlequin 2.0 population genetics software, the Fixation index (F ST) was found to be 0.09994, thus demonstrating that the observed variability is mainly within (90.006%) and not among (9.994%) populations (P < 0.00001). Moreover, the global test of differentiation demonstrated that every population differs from each other (P < 0.00325). Finally, the Ewens-Watterson test of selective neutrality yielded to statistical significance in only 3 populations. In conclusion, Turkish FMF patients are characterized by an increased genetic heterogeneity, explained by the intrapopulation differentiation. Thus, the regional origin should be regarded as a determining factor in the diagnosis of FMF in Turkish patients.