Longer survival associated with HLA‐A*03, B*14 among 212 hemochromatosis probands with <i>HFE</i> C282Y homozygosity and HLA‐A and ‐B typing and haplotyping<sup>1</sup>

Barton, James C.; Acton, Ronald T.

doi:10.1111/j.1600-0609.2010.01511.x

Cited by 8 publications

(5 citation statements)

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“…A*03 positivity and allele frequency did not differ significantly in men and women grouped by the highest and lowest three quartiles of QFe/age. Consistent with the present findings, A*03 was not a significant modifier of survival in Alabama hemochromatosis probands with p.C282Y homozygosity [ 37 ]. Taken together, these observations demonstrate that A*03, the only known independent marker of the hemochromatosis AH [ 9 , 13 – 15 , 38 ], is not linked to a putative A*03-linked locus that significantly influences iron overload or related conditions in Alabama p.C282Y homozygotes, contrary to previous postulates [ 13 – 16 ].…”

Section: Discussionsupporting

confidence: 89%

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

Barton

Acton

2022

Hereditas

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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.

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Section: Discussionsupporting

confidence: 89%

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

Barton

Acton

2022

Hereditas

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“…Decreased overall survival was significantly associated with heavy ethanol consumption and cirrhosis. These outcomes are consistent with previous reports of survival of patients with hemochromatosis unselected for diagnoses of ACs [ 11 , 22 , 96 ].…”

Section: Discussionsupporting

confidence: 92%

“…The gene, now known as HFE , occurs in linkage disequilibrium with the HLA-A locus [ 3 , 7 , 8 ]. The most common hemochromatosis ancestral haplotypes in many northwestern European and derivative populations include HFE C282Y linked to HLA-A ∗ 03 [ 7 – 10 ], HLA-A ∗ 03, B ∗ 07 [ 7 – 9 ], or HLA-A ∗ 03, B ∗ 14 [ 7 – 9 , 11 ]. C282Y also occurs on other HLA haplotypes, including A ∗ 01, B ∗ 08 and A ∗ 29, B ∗ 44 [ 7 , 8 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Conditions in 235 Hemochromatosis Probands withHFEC282Y Homozygosity and Their First-Degree Relatives

Barton

2015

Journal of Immunology Research

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We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.

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“…43,44 Interestingly, some HLA haplotypes (such as HLA-A*03, B*14) may confer longer survival in C282Y homozygotes due to earlier age of diagnosis and less-severe iron loading phenotype. 45 HFE gene mutations have also been implicated as risk factors for malignancy. H63D homozygosity results in a threefold increase in incidence and earlier age of onset of colorectal cancer in MMR gene mutation-carriers.…”

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Natural History and Management ofHFE-Hemochromatosis

2011

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Advances in our knowledge of hereditary hemochromatosis (HH) over the past 150 years have revealed new insights into this common genetic disorder. Meticulous family and HLA association studies followed ultimately by cloning of the HFE gene have dramatically changed our understanding of the natural history and manifestations of HH. Cross-sectional studies demonstrated that HH had a highly variable clinical and biochemical penetrance in susceptible individuals of northern European descent. "State-of-the-art" large longitudinal population studies have accurately defined the natural history. We now recognize that HH is not as discreet an entity as previously thought because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical course of HH. While phlebotomy remains the cornerstone of therapy, our diagnostic approach has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches. This review aims to encapsulate this new knowledge in a framework that addresses commonly raised issues relating to the current natural history, diagnosis, and management of HH patients.

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Longer survival associated with HLA‐A03, B14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA‐A and ‐B typing and haplotyping¹

Abstract: In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A03, B14. Earlier age at diagnosis and less severe iron overload in probands with A03, B14 could explain this difference.

Cited by 8 publications

References 42 publications

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

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

Autoimmune Conditions in 235 Hemochromatosis Probands withHFEC282Y Homozygosity and Their First-Degree Relatives

Natural History and Management ofHFE-Hemochromatosis

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Longer survival associated with HLA‐A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA‐A and ‐B typing and haplotyping1

Abstract: In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A*03, B*14. Earlier age at diagnosis and less severe iron overload in probands with A*03, B*14 could explain this difference.

Cited by 8 publications

References 42 publications

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

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

Autoimmune Conditions in 235 Hemochromatosis Probands withHFEC282Y Homozygosity and Their First-Degree Relatives

Natural History and Management ofHFE-Hemochromatosis

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Longer survival associated with HLA‐A03, B14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA‐A and ‐B typing and haplotyping¹

Abstract: In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A03, B14. Earlier age at diagnosis and less severe iron overload in probands with A03, B14 could explain this difference.