Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda

Background Sporadic porphyria cutanea tarda is a skin disease associated with hepatic siderosis. Depletion of iron stores by phlebotomy is curative. The role of haemochromatosis genes in determining susceptibility to this disorder is controversial, We have examined the frequency in sporadic porphyria cutanea tarda of mutations (Cys282Tyr, His63Asp) in a novel MHC class-I-like gene, one of which (Cys282Tyr) is believed to cause haemochromatosis. Methods 41 patients with sporadic porphyria cutanea tarda, in whom the frequency of microsatellite alleles that define the ancestral haemochromatosis haplotype had previously been determined, and 101 healthy blood donors were studied for the presence of the Cys282Tyr and His63Asp mutations. We used restriction-enzyme digestion of PCR-amplified genomic DNA. Findings The Cys282Tyr mutation occurred in 18 (44%) of patients compared with 11 (11%) of controls (relative risk 6.2, 95% CI 2.6-14.5, p=0.00003). Seven (17%) patients, aged 48-79 years, were homozygotes. In 12 patients, the Cys282Tyr mutation was associated with markers of the HLA-A3-containing ancestral haemochromatosis haplotype. Ages at presentation were the same for those with or without the Cys282Tyr mutation. There was no difference in the frequency of the His63Asp mutation. Interpretation Inheritance of one or more haemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda. Some homozygotes for the Cys282Tyr mutation present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with haemochromatosis. The relation between this genotype and disease needs further investigation.