Linkage disequilibrium analysis in Australian haemochromatosis patients indicates bipartite association with clinical expression

Background/Aims:Hereditary haemochromatosis shows a wide variation in phenotypic expression, which is thought to be due, in part, to genetic factors. A single missense mutation in HFE, leading to an amino acid substitution (C282Y) has been shown to be the causative mutation, clearly responsible for clinical expression of the disorder. Since homozygosity for the C282Y mutation can give rise to a disorder which shows wide variation in clinical expression, we investigated the possibility that genetic modifiers of HFE may exist. Methods: Linkage disequilibrium analysis was performed on chromosome 6p21,3 in 74 patients homozygous for the C282Y mutation using microsatellite markers spanning the haemochromatosis gene region. Phenotypic expression was evaluated based on transferrin saturation, serum ferritin, hepatic iron concentration and index, and iron grade. Results: Linkage disequilibrium (LD) analysis showed a predominant ancestral haplotype from D6S265 to D6S2236 covering a region of approximately 5 Mb. The overall LD distribution in this region showed two peaks of highly significant association at D6S105 (2 Mb proximal to HFE) and at D6S2239 approximately 50 kb distal to HFE. Male patients homozygous for D6S105 allele 8, had significantly higher hepatic iron indices than patients heterozygous or nullizygous for D6S105-8 (