ALLELIC ASSOCIATION OF MICROSATELLITES OF 6P IN ITALIAN HEMOCHROMATOSIS PATIENTS

Hemochromatosis (HC) is an inherited disorder of iron metabolism and i s frequently seen in Caucasians. The biochemical defect and the respon sible gene are unknown, but the HC locus is closely linked to HLA-A on human chromosome 6 in the region 6p21.3. Although extensive studies h ave been performed in several populations, the precise location of the gene is still undefined. Linkage disequilibrium with HC has been dete cted for loci that are 3 cM apart: HLA class I and D6S105, which is lo cated on the telomeric side of HLA-A. We have analyzed the inheritance of several multi-allele polymorphisms that map to 6p (D6S265, Y52, HL A-F, D6S306, D6S105, D6S464, D6S299) in 34 Italian HC families and in 17 unrelated patients. Significant association with HC was shown for a lleles of multiple markers in the HLA-A region, For the distant marker D6S105, but not for the D6S299 marker at 3 cM from HLA-A on the telom eric side. HC status was unambiguously assigned to 70 affected and 63 unaffected chromosomes from family studies. Thirty five different hapl otypes were found in 70 HC chromosomes when considering four markers m ost tighly associated with the disease. A predominant haplotype compri sing alleles 1-3-1-8 (marker order D6S265, HLA-A, Y52, D6S105) account ed for 30% of the HC chromosomes and was absent in normals. A minority of other HC haplotypes could be related to the major haplotype by ass uming single crossover events. Results of haplotype studies suggest a founder effect in the Italian population, as previously shown in Austr alian patients, and a possible common mutation shared with affected in dividuals of Celtic origin.