Histocompatibility antigens as markers of abnormal iron metabolism in patients with idiopathic haemochromatosis and their relatives.

HLA-A3 was significantly more common in 35 unrelated patients with idiopathic haemochromatosis (69%) than in 95 controls (31%). Further studies in two families suggest that 2 genes are involved in the pathogenesis of the disease, each associated with a separate metabolic defect. Whereas minor abnormalities, namely raised serum-iron and some increase in storage iron, were found in relatives with an HLA A11, B27, CW2 haplotype, those with the A3, B14, CW5 haplotype had no detectable abnormalities. When both these haplotypes were found together, as in the propositus and one sibling in the first family investigated, all the signs of the fully developed disease were apparent. It is suggested that one of the genes is in linkage disequilibrium with HLA-A3 and could be responsible for a kinetic abnormality, possibly increased plasma to storage iron exchange. The other gene, also carried on the sixth chromosome and, in the first family, marked by the HLA A11, B27, CW2 haplotype might result in an increased absorption of dietary iron. The concomitant inheritance of these two genes and the metabolic defects they determine are required for the full development of the disease