HLA-A*03, the hemochromatosis ancestral haplotype, and phenotypes of referred hemochromatosis probands with HFE p.C282Y homozygosity.

Abstract

BACKGROUND:

Human leukocyte antigen (HLA)-A*03, hemochromatosis ancestral haplotype marker, was associated with greater iron overload in hemochromatosis cohorts reported before discovery of the HFE gene. We sought to learn whether an A*03-linked locus influences phenotypes in referred HFE p.C282Y homozygotes.

METHODS:

We tabulated these phenotypes in probands with p.C282Y homozygosity: age, transferrin saturation (TS), serum ferritin (SF), conditions related to iron overload, fibrosis-four variables (FIB-4) index and aspartate aminotransferase-to-platelet ratio index (APRI) predictors of severe hepatic fibrosis, and iron removed to achieve depletion (QFe/age). We analyzed phenotypes of men and women separately across three A*03 subgroups.

RESULTS:

There were 104 men (57.8%) and 76 women (42.2%). Mean age (SD) was 49 ± 13 y. Mean TS was 79 ± 17%. Median SF (range) was 715 µg/L (28, 6103). Related conditions included: hemochromatosis arthropathy (21.7%); type 2 diabetes (18.9%); hypogonadotropic hypogonadism (5.8% of men); cardiomyopathy (0%); and cirrhosis (10.0%). Median QFe/age was 61 mg/y (0, 714). A*03 homozygosity, heterozygosity, and no A*03 occurred in 37 (20.6%), 104 (57.8%), and 39 probands (21.7%), respectively. In men, mean TS and median SF were significantly higher in A*03 homozygotes than heterozygotes but not A*03-negative probands. In men, median APRI was significantly lower in A*03 heterozygotes than homozygotes and A*03-negative probands. No other phenotypes, including QFe/age, differed significantly across A*03 subgroups in either men or women.

CONCLUSIONS:

Our results suggest that an A*03-linked locus does not influence phenotypes in referred HFE p.C282Y homozygotes. It is unlikely that heritable factors that modify phenotypes of p.C282Y homozygotes are linked to the hemochromatosis ancestral haplotype.

• Authors: James C Barton, J Clayborn Barton, Ronald T Acton
• Journal: Hereditas (Hereditas) Vol. 159 Issue 1 Pg. 25 (Jun 06 2022) ISSN: 1601-5223 [Electronic] England
• PMID: 35659379 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• HFE protein, human
• HLA-A Antigens
• Hemochromatosis Protein
• Histocompatibility Antigens Class I
• Membrane Proteins

Topics

• Diabetes Mellitus, Type 2 (complications)
• Female
• HLA-A Antigens (genetics)
• Haplotypes
• Hemochromatosis (genetics)
• Hemochromatosis Protein (genetics)
• Histocompatibility Antigens Class I (genetics)
• Homozygote
• Humans
• Iron Overload (complications, genetics)
• Membrane Proteins (genetics)
• Phenotype