Tags

Type your tag names separated by a space and hit enter

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.
Eur J Haematol. 2010 Feb 01; 84(2):145-53.EJ

Abstract

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/km(2).

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.

Authors+Show Affiliations

Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Göteborg, SE- 413 45 Göteborg, Sweden. sigvard.olsson@medic.gu.seNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19912313

Citation

Olsson, K Sigvard, et al. "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, vol. 84, no. 2, 2010, pp. 145-53.
Olsson KS, Ritter B, Raha-Chowdhury R. 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. Eur J Haematol. 2010;84(2):145-53.
Olsson, K. S., Ritter, B., & 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(2), 145-53. https://doi.org/10.1111/j.1600-0609.2009.01376.x
Olsson KS, Ritter B, Raha-Chowdhury R. 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. Eur J Haematol. 2010 Feb 1;84(2):145-53. PubMed PMID: 19912313.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Olsson,K Sigvard, AU - Ritter,Bernd, AU - Raha-Chowdhury,Ruma, Y1 - 2009/11/12/ PY - 2009/11/17/entrez PY - 2009/11/17/pubmed PY - 2010/2/26/medline SP - 145 EP - 53 JF - European journal of haematology JO - Eur J Haematol VL - 84 IS - 2 N2 - 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/km(2). 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. SN - 1600-0609 UR - https://www.unboundmedicine.com/medline/citation/19912313/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_ L2 - https://doi.org/10.1111/j.1600-0609.2009.01376.x DB - PRIME DP - Unbound Medicine ER -