Present address Mälar Hospital, Eskilstuna, Sweden;
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
Version of Record online: 12 NOV 2009
© 2009 John Wiley & Sons A/S
European Journal of Haematology
Volume 84, Issue 2, pages 145–153, February 2010
How to Cite
Olsson, K. S., Ritter, B. and Raha-Chowdhury, R. (2010), 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. European Journal of Haematology, 84: 145–153. doi: 10.1111/j.1600-0609.2009.01376.x
- Issue online: 4 JAN 2010
- Version of Record online: 12 NOV 2009
- Accepted for publication 8 November 2009
- HFE mutation (H, human; Fe, iron);
- iron overload;
- human leucocyte antigen;
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.