The MICA region determines the first modifier locus in familial Mediterranean fever

Objective.Familial Mediterranean fever (FMF) is a genetically recessive inflammatory disease caused by mutations in the MEFV gene.Most patients of non-Ashkenazi Jewish ancestry or those who are homozygous for M694V manifest a severe disease course, but some express a mild form of the disease.We therefore searched for other genes which could possibly be implicated in the disease phenotype.We tested MICA (major histocompatibility complex class I chain-related gene A) because it has been associated with a number of other inflammatory disorders.Methods.One hundred fifty FMF probands and their family members were evaluated.The MEFV gene was screened by a combination of denaturing gradientgel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system.The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products were loaded onto sequencing gels and subjected to autoradiography. Results.The contribution of MICA to the FMF phenotype was confirmed after adjustment for the patient's ancestry and for the MEFV genotype.MEFV was individually the most important prognostic factor for the disease.However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was aggravated if patients also inherited MICA-A9 (OR 6.3).In contrast, the frequency of attacks was found to be dramatically reduced (OR 0.16) in patients with MICA-A4. Conclusion.We have identified the first FMF modifier locus, MICA.FMF is the first model of a Mendelian disease associated with MICA.These results clarify, at least partly, the inconsistent phenotype-MEFV correlation in FMF.Familial Mediterranean fever (FMF) is an inflammatory disorder with symptoms that include recurrent febrile attacks, synovitis, and cutaneous signs.It mainly affects populations of Mediterranean ancestry (1) and is especially severe in non-Ashkenazi Jews (NAJs) (2).To date, more than 20 mutations have been detected in the gene responsible for FMF (MEFV) (3-8).The role of the corresponding protein (marenostrin/pyrin) is still unknown.The discovery of MEFV has provided the first specific biologic tool for the diagnosis of FMF.Indeed, FMF can be accurately pinpointed among various inflammatory disorders through MEFV mutation screening.However, screening alone cannot be used as a prognostic test because of the lack of complete correlation between the clinical features of the disease and the MEFV mutations (6-9).Currently, the clearest available data concerning phenotype-genotype relate to M694V, the most frequent FMF mutation.M694V accounts for 70-90% of the FMF chromosomes in NAJs and for 30-60% of those in other populations.Homozygosity for M694V has been reproducibly demonstrated to be associated with a severe disease course in NAJs and Armenians (2,8,10-13), but not in Turks (9).This genotype is practically fully penetrant.The greater disease severity in NAJs has therefore been attributed to the higher M694V frequency in this population.M694Vhomozygous patients may nevertheless display a wide array of clinical features, ranging from rare isolated bouts of fever to severe renal amyloidosis with dramatic