Global prevalence of putative haemochromatosis mutations.

TLDR

Haemochromatosis, a genetic iron‑overload disorder common in northern Europeans, is linked to two HLA‑H mutations, C282Y and H63D, with most UK patients homozygous for C282Y. The study genotyped 5,956 chromosomes from 2,978 individuals using PCR and restriction enzyme analysis to detect HLA‑H C282Y and H63D variants. Worldwide, C282Y occurs in 1.9 % of chromosomes (up to 10 % in Irish) and H63D in 8.1 % (up to 30.4 % in Basque), with C282Y absent in African, Asian, and Australasian populations, aligning with haemochromatosis prevalence and suggesting a north‑European origin, while H63D’s broader distribution leaves its disease association uncertain.

Abstract

Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin. HLA-H is a recently reported candidate gene for this condition. Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187). Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation. We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis. We have found world wide allele frequencies of 1.9% for C282Y and 8.1% for H63D. The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 30.4% for H63D in 56 Basque chromosomes. C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes. The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation. The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear.