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

Objective. Familial Mediterranean fever (FMF) is a genetically recessive in flammatory disease caused by mutations in the MEFV gene. Most patients of n on-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 t herefore 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 oth er inflammatory disorders. Methods. One hundred fifty FMF probands and their family members were evalu ated. The MEFV gene was screened by a combination of denaturing gradient-ge l electrophoresis, restriction fragment length polymorphism, and amplificat ion refractory mutation system. The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products wer e 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 i ndividually the most important prognostic factor for the disease. However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was a ggravated if patients also inherited MICA-A9 (OR 6.3). In contrast, the fre quency of attacks was found to be dramatically reduced (OR 0.16) in patient s,vith MICA-A4, Conclusion. We have identified the first FMF modifier locus, MICA, FMF is t he first model of a Mendelian disease associated with MICA, These results c larify, at least partly, the inconsistent phenotype-MEFV correlation in FMF ..