title: Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?
abstract: The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8(+) T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.
authors.affiliation: Molecular Immunology and Pathology, Abel Salazar Institute for the Biomedical Sciences, Lg. Prof. Abel Salazar 2, 4050 Porto, Portugal.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Cardoso
authors.forename: Helena
authors.initials: H
authors.lastname: Alves
authors.forename: Mónica
authors.initials: M
authors.lastname: Mascarenhas
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gonçalves
authors.forename: Pedro
authors.initials: P
authors.lastname: Oliveira
authors.forename: Pedro
authors.initials: P
authors.lastname: Rodrigues
authors.forename: Eugénia
authors.initials: E
authors.lastname: Cruz
authors.forename: Maria
authors.initials: M
authors.lastname: de Sousa
authors.forename: Graça
authors.initials: G
authors.lastname: Porto
mesh_terms: D000483:Alleles; D005075:Biological Evolution; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005787:Gene Frequency; D006680:HLA Antigens / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics*; D006239:Haplotypes; D006432:Hemochromatosis / Q000235:genetics / Q000276:immunology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008565:Membrane Proteins; D017354:Point Mutation; D012641:Selection, Genetic
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D015234:HLA-A Antigens; C035524:HLA-A29 antigen; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins