HLA-A3-B14 and the origin of the haemochromatosis C282Y mutation: founder effects and recombination events during 12 generations in a Scandinavian family with major iron overload

Background: The haemochromatosis mutation C282Y occurred once in a person who lived in Ireland or Scandinavia and carried either human leucocyte antigen (HLA)-A3-B7 or A3-B14. With time, recombinations are believed to have taken place introducing new HLA haplotypes. This evolution is mainly unknown. In this study, we tried to find a founder, possible recombination events and effect on the phenotype in descendants. Setting: A Swedish mountain population close to Norway, n = 3529, population density < 1/km2. Methods: Retrospective genealogy study of HLA haplotypes followed by extended haplotype studies. Results: There were 34 probands (22 men, 12 women) where 31 (91%) shared a common founder origin 12 generations ago. The A3-B14 haplotype was the most common, 39%, in strong linkage disequilibrium (P < 0.0005) with controls, followed by A3-B7, 20% (P < 0.005), probably resulting from a centromeric recombination replacing the B14 allele with the common B7. Possible telomeric recombinations took place close to HLA-A and introduced the haplotypes AW19-B7 (n = 4), AW19-B27 (2), A1-B17 (5) and A2-B12 (4) supported by pedigree studies. Male homozygotes with two copies of HLA-A3 had significantly (P 0.001) higher mean serum ferritin values than those with one, and liver damage (fibrosis and cirrhosis) was also more common (P < 0.001) than in a population with a recombinant (A1-B8) haplotype. Conclusions: A3-B14 may well be the ancestral haplotype with A3B7, the result of centromeric recombinations introducing the common B7 allele. Telomeric recombinations were more common than expected. The ancestral HLA-A3 haplotype may be associated with a more severe phenotypic expression.