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.