A High-Resolution Genetic Map of the Familial Mediterranean Fever Candidate Region Allows Identification of Haplotype-Sharing among Ethnic Groups

James E. Balow, David A. Shelton, Annette Orsborn, Marie Mangelsdorf, Ivona Aksentijevich, Trevor Blake, Raman Sood, Dawn Gardner, Raymond Liu, Elon Pras, Ernesto N. Levy, Michael Centola, Zuoming Deng, Nurit Zaks, Geryl Wood, Xiaoguang Chen, Neil Richards, Mordechai Shohat, Avi Livneh, Mordechai Pras, Norman A. Doggett, Francis S. Collins, P.Paul Liu, Jerome I. Rotter, Nathan Fischel-Ghodsian, Deborah Gumucio, Robert I. Richards, Daniel L. Kastner

Familial Mediterranean fever (FMF) is a recessive disorder of inflammation caused by mutations in a gene (designated MEFV) on chromosome 16p13.3. We have recently constructed a 1-Mb cosmid contig that includes the FMF critical region. Here we show genotype data for 12 markers from our physical map, including 5 newly identified microsatellites, in FMF families. Intrafamilial recombinations placed MEFV in the approximately 285 kb between D16S468/D16S3070 and D16S3376. We observed significant linkage disequilibrium in the North African Jewish population, and historical recombinants in the founder haplotype placed MEFV between D16S3082 and D16S3373 (approximately 200 kb). In smaller panels of Iraqi Jewish, Arab, and Armenian families, there were significant allelic associations only for D16S3370 and D16S2617 among the Armenians. A sizable minority of Iraqi Jewish and Armenian carrier chromosomes appeared to be derived from the North African Jewish ancestral haplotype. We observed a unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians and two other haplotypes restricted to either the Iraqi Jewish or the Armenian population. These data support the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another.