Linkage disequilibrium between HLA haplotypes and HFE mutations in the portuguese population

• Type: Article in International Scientific Journal
• Date: 2001

Authors

alves, h (Author) Other; cardoso, c (Author) Other; rodrigues, p (Author) Other; porto, g (Author) ICBAS

Journal

Title: European Journal of Immunogenetics

Vol. 28

Pages: 301-301

ISSN: 0960-7420

Publisher: Blackwell

Indexing

ISI Web of Knowledge

Scopus - 0 Citations

Other information

Authenticus ID: P-007-G95

Abstract (EN): Introduction: The well known linkage disequilibrium (LD) found between some particular HLA antigens in human populations suggests a convergent evolution where selective forces must be involved. Response to external pathogens is classically assumed as an important one, but fails as an unique explanation. The discovery of HFE, a new MHC class-1 gene involved in iron metabolism, brought a new player into the scene. Confirming previous findings of HLA/hemochromatosis association, the HFE mutation C282Y was found in strong LD with the haplotype A3-B7. In 1998 we described, for the first time, an association between the HFE mutation H63D and the haplotype A29-B44. This finding suggested the existence of at least two distinct HLA ancestral haplotypes related with iron overload. To extend this question we have now analysed a Portuguese population of hemochromatosis families and control families for HFE/HLA, associations. Material and Methods: a) A total of 223 subjects screened for hemochromatosis, HFE and HLA typed: 43 patients, 51 family members without iron overload and 129 healthy subjects, b) From an additional sample of 587 non-related HLA haplotyped normal subjects, we selected for HFE genotyping 56 carriers of A3-positive haplotypes, 48 carriers of A29-positive haplotypes and, as controls, subjects B7+/A3- (11) and B44+/A29-(112). Results: In the population screened for iron overload, the HLA antigen frequencies A3+B7 appeared significantly associated with the C282Y mutation (p=0.0015) and the A29+B44 with the H63D mutation (p=0.001). No associations were found in subjects without HFE mutations. HLA B-A-HFE haplotypes were defined in 43 families of patients with iron overload (44 chromosomes with C282Y, 26 with H63D and 80 wild type). A strong linkage was found for haplotypes: A3-C282Y, B7-A3-C282Y and A29-H63D (p<0.005), and B44-A29-H63D (p=0.01). No significant linkage was observed in chromosomes with wild type alleles. In normal random families, increased frequencies of C282Y and H63D were found respectively in carriers of haplotypes A3-B7 and A29-B44. Discussion: The finding that the conservation of particular HLA haplotypes is associated to the presence of HFE mutations, not only in hemochromatosis families but also in the random population, suggests a possible co-selection of the two loci, and reflects their involvement in an important common biological pathway: iron metabolism. The iron overload associated to the HFE mutations could have worked as a selective force in human evolution during critical periods of low iron supply, and explain the actual high frequency of the mutations in the normal Caucasian population. © 2001 Blackwell Science Ltd,.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 1