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HFE hemochromatosis in African Americans: Prevalence estimates of iron overload and iron overload-related disease

Published:September 09, 2022DOI:https://doi.org/10.1016/j.amjms.2022.08.015

      Abstract

      Background

      Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA).

      Methods

      We defined AA as self-identified AA, blacks, or non-Hispanic blacks. We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D. We compiled prevalences of these genotypes in AA using published population and cohort data and numbers of men and women ≥18 y‬ in 2018 U.S. Census estimates. We defined iron overload (IO) and IO-related disease by genotype as previously reported in population and cohort studies of hemochromatosis in whites of European ancestry. We used these definitions to estimate prevalences and numbers of AA with IO and IO-related disease associated with hemochromatosis-associated HFE genotypes.

      Results

      There were ∼16,287,599 men and ∼17,644,898 women. HFE genotypes and their respective prevalences were: p.C282Y/p.C282Y, 0.00017 (6/34,905) [95% confidence interval 0.000034, 0.00031] and p.C282Y/p.H63D, 0.0012 (41/33,596) [0.000084, 0.0016]. IO prevalences were: men 0.000076 [0.000072, 0.000081] and women 0.0000061 [0.0000050, 0.0000073]. IO-related disease prevalences were: men 0.000063 [0.000059, 0.000067] and women 0.0000021 [0.0000014, 0.0000027]. There were ∼1021 [961, 1091] men and ∼36 [25, 48] women with IO-related disease.

      Conclusions

      We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/32,103 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.

      Key Indexing Terms

      Introduction

      Hemochromatosis is a cosmopolitan group of disorders characterized by increased absorption of dietary iron,
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      ,
      • Ganz T.
      Hepcidin and iron regulation, 10 years later.
      increased risk of iron overload (IO) with consequent tissue injury,
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      and inappropriately low levels of hepcidin, the central controller of iron absorption.
      • Ganz T.
      Hepcidin and iron regulation, 10 years later.
      In 1996, it was discovered that the most common hemochromatosis subtype is due to homozygosity for the p.C282Y allele (exon 4, c.845G>A; rs1800562) of HFE (homeostatic iron regulator, chromosome 6p22.2).
      • Feder JN
      • Gnirke A
      • Thomas W
      • et al.
      A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
      Most p.C282Y homozygotes are whites who reside in western Europe and derivative countries including Australia, Canada, and the U.S.
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      ,
      • Barton JC
      • Edwards CQ
      • Acton RT.
      HFE gene: Structure, function, mutations, and associated iron abnormalities.
      Typical hemochromatosis laboratory phenotypes of untreated adults with HFE p.C282Y homozygosity include elevated transferrin saturation (TS), elevated serum ferritin (SF) levels, and increased iron in hepatocytes.
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      Complications of IO occur in some patients with p.C282Y homozygosity, including arthropathy, diabetes, hypogonadism, elevated serum concentrations of hepatic transaminases, hepatic fibrosis, and cirrhosis.
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      IO also occurs in some persons with p.C282Y in compound heterozygosity with HFE p.H63D (exon 2, c.187C>G, rs1799945).
      • Gurrin LC
      • Bertalli NA
      • Dalton GW
      • et al.
      HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.
      A 1991 report described an African-American man with hemochromatosis, severe hepatocyte iron loading, cirrhosis, and human leukocyte antigens A*03 and B*07 suggestive of HFE hemochromatosis.
      • Conrad ME.
      Sickle cell disease and hemochromatosis.
      In 2001-2005, there were reports of referred African-American patients with hemochromatosis phenotypes who had either HFE p.C282Y homozygosity
      • Barton JC
      • Acton RT.
      Inheritance of two HFE mutations in African Americans: cases with hemochromatosis phenotypes and estimates of hemochromatosis phenotype frequency.
      or p.C282Y/p.H63D compound heterozygosity.
      • Barton JC
      • Acton RT.
      Inheritance of two HFE mutations in African Americans: cases with hemochromatosis phenotypes and estimates of hemochromatosis phenotype frequency.
      ,
      • Labowitz DA
      • Bontreger J
      • Min AD.
      An unusual case of hemochromatosis in an African-American man: case report and review of the literature.
      In 27,124 self-identified black participants in a primary care-based North American hemochromatosis and iron overload screening study, the prevalence of HFE p.C282Y homozygosity was 0.00011.
      • Barton JC
      • Acton RT
      • Dawkins FW
      • et al.
      Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.
      In the same cohort, the prevalence of p.C282Y/p.H63D compound heterozygosity was 0.0013.
      • Barton JC
      • Acton RT
      • Dawkins FW
      • et al.
      Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.
      There is no reported prevalence estimate of IO in African Americans (AA) with hemochromatosis-associated HFE genotypes, without or with IO-related disease.
      We sought to estimate the prevalences and numbers of African-American men and women with hemochromatosis-associated HFE genotypes who have IO without and with IO-related disease. We compiled reports of the prevalences of hemochromatosis-associated HFE genotypes p.C282Y/p.C282Y and p.C282Y/p.H63D in AA using data from population and cohort studies identified by computerized searches of medical literature. We computed numbers of African-American men and women ≥18 y using 2018 U.S. Census estimates. We estimated numbers of African-American men and women with IO without and with IO-related disease using proportions of whites of European ancestry with IO without and with IO-related disease in population studies and classified by hemochromatosis-associated HFE genotypes. We discuss the relative contribution of HFE genotypes to non-transfusion IO in AA.

      Methods

      Ethics statement

      This work was performed according to the principles of the Declaration of Helsinki.
      World Medical Association
      Declaration of Helsinki: ethical principles for medical research involving human subjects.
      Western Institutional Review Board granted an exemption for performance of this study under 45 CFR46.101(b)(4) on 4 March 2019 (submission no. 2554968-44265830). This study is based entirely on compilation and analyses of published data. There was no direct involvement of human subjects.

      Data sources

      We performed computerized literature searches of The National Library of Medicine and the internet using the terms AA, black, European Americans (EA), hemochromatosis, HFE, IO, National Health and Nutrition Examination Survey (NHANES), p.C282Y, penetrance, p.H63D, screening, U.S. Census 2018, and white. We reviewed pertinent publications. Our computerized searches encompassed the interval August 1996 - August 2021. We compiled prevalences of hemochromatosis-associated HFE genotypes in AA and EA from U.S. population and cohort screening studies.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      We excluded p.C282Y and p.H63D data for “Africans” from the Genome Aggregation Database because the Database displays combined observations in sub-Saharan African blacks and AA.

      Karczewski KJ, Franciola LC, Tiao G, et al. Cold Spring Harbor Laboratory. The mutational constraint spectrum quantified from variation in 141,456 humans, https://doi.org/10.1101/531210; 2020 [accessed 5.22.20].

      Definition of African Americans

      AA, defined herein as self-identified AA, blacks, or non-Hispanic blacks, are persons who descended from enslaved black Africans taken from broad contiguous areas of sub-Saharan West Africa and brought to the region of the present U.S.
      • Lovejoy PE.
      Transformations in Slavery.

      Definition of European Americans

      EA, defined herein as self-identified EA, whites, non-Hispanic whites, or Caucasians, are persons with predominantly white European ancestry who reside in the U.S.

      Definition of hemochromatosis-associated HFE genotypes

      We defined hemochromatosis-associated HFE genotypes as p.C282Y/p.C282Y and p.C282Y/p.H63D.
      • Edwards CQ
      • Barton JC.
      Hemochromatosis.
      ,
      • Feder JN
      • Gnirke A
      • Thomas W
      • et al.
      A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.

      Definition of documented iron overload

      We defined documented IO as one or more of the following, according to the criteria of Allen et al.: hepatic iron staining grade 3 or 4, hepatic iron concentration >90 µmol/g, hepatic iron index >1.9, or SF >1000 µg/L at baseline with documented therapeutic venesection.
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.

      Definition of iron overload-related disease

      We defined IO-related disease according to the criteria of Allen et al.
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.
      This definition requires demonstration of documented IO and at least one of the following five features: tenderness or effusion of the second and third metacarpophalangeal joints, elevated serum concentrations of alanine and aspartate aminotransferase (>40 IU/L and >45 IU/L, respectively), fibrosis or cirrhosis proven on percutaneous liver biopsy, hepatocellular carcinoma, or diagnosis by a physician due to symptoms associated with hereditary hemochromatosis.

      Prevalence of HFE p.C282Y/p.C282Y and p.C282Y/p.H63D in African and European Americans

      We tabulated the prevalence of HFE p.C282Y/p.C282Y (nine studies) and p.C282Y/p.H63D (eight studies) in parallel populations and cohorts of AA and EA unselected for possible hemochromatosis or IO. These data are displayed in an open-access database.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.

      Documented iron overload and hemochromatosis-associated HFE genotypes

      We found no published estimate of the proportion of AA with documented IO and hemochromatosis-associated HFE genotypes in large-scale studies. Thus, we used HFE genotype-specific percentages of men and women with documented IO, without and with IO-related disease, determined in population screening and clinical cohort studies of adults of European ancestry (Table 1).
      • Gurrin LC
      • Bertalli NA
      • Dalton GW
      • et al.
      HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.
      ,
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.
      Table 1Documented iron overload and hemochromatosis-associated HFE genotypes in population studies of adults of European ancestry in Australia
      These estimates were based on studies of participants in population screening programs.
      .
      HFE genotypeMen with documented iron overload, %Men with iron overload-related disease, %Women with documented iron overload, %Women with iron overload-related disease, %RegionReference
      p.C282Y/p.C282Y36.528.43.61.2AustraliaAllen et al.
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.
      p.C282Y/p.H63D1.21.200AustraliaAllen et al.
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.
      ; Gurrin et al.
      • Gurrin LC
      • Bertalli NA
      • Dalton GW
      • et al.
      HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.
      a These estimates were based on studies of participants in population screening programs.

      Statistics

      We tabulated prevalences of hemochromatosis-associated HFE genotypes in AA and EA using data compiled from published sources and displayed them in an open-access database.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      All prevalence data herein are displayed as decimal fractions of two significant figures. We assumed that all HFE genotypes occur in equal proportions of men and women of the same ancestry and that documented IO, without or with IO-related disease, occurs exclusively in adults ≥18 y. We assumed that the prevalence of documented IO, without or with IO-related disease, in AA with hemochromatosis-associated HFE genotypes is the same as it is in whites of European ancestry with corresponding HFE genotypes. We used prevalences of HFE genotypes [95% confidence interval (CI)] and prevalences of documented IO, without or with IO-related disease (Table 1), to estimate aggregate prevalences [95% CI] and mean numbers [95% CI] of African-American men and women with documented IO without and with IO-related disease.
      Descriptive data are displayed as n, enumerations, and prevalences [95% CI]. Proportions were compared using Fisher's exact test (two-tailed) or Pearson's Chi-square test with Yates correction (two-tailed), as appropriate. Values of p < 0.05 were defined as significant. Analyses were performed with Excel 2000® (Microsoft Corp., Redmond, WA, USA) and GraphPad Prism 8® (GraphPad Software, San Diego, CA, USA).

      Results

      Numbers of African-American adults

      In 2018 U.S. Census estimates, there were ∼33,932,497 African-American adults ≥18 y (77.4% of 2018 African-American population) (48% men, 52% women).

      United States Census Bureau, Population Division. Annual Estimates of the Resident Population: April 1, 2010 to July 1, 2018: 2018 Population Estimates,https://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?src=bkmk; 2018 [accessed 8.3.21 A.D.].

      ,

      United States Census Bureau, Department of Commerce. Quick Facts. United States,https://www.census.gov/quickfacts/fact/table/US/IPE120217; 2019 [accessed 8.3.21].

      Prevalences of hemochromatosis-associated HFE genotypes

      Aggregate prevalences of HFE p.C282Y/p.C282Y and p.C282Y/p.H63D are significantly lower in AA than EA (Table 2). The aggregate prevalence of p.C282Y/p.C282Y was 28.2-fold greater in EA than AA. The aggregate prevalence of p.C282Y/p.H63D was 16.7-fold greater in EA than AA.
      Table 2Aggregate prevalences of hemochromatosis-associated HFE genotypes in population and cohort studies
      Sources and components of these data are displayed in an open-access database.11 CI, confidence interval.
      .
      HFE genotypePrevalence in African Americans (n) [95% CI]Prevalence in European Americans (n) [95% CI]Value of pAfrican American/European American prevalence, %
      p.C282Y/p.C282Y0.00017 (6/34,905) [0.000034, 0.00031]0.0048 (331/68,854) [0.0043, 0.0053]<0.00014.0
      p.C282Y/p.H63D0.0012 (41/33,956) [0.00084, 0.0016]0.020 (1343/65,627) [0.019, 0.022]<0.00016.0
      a Sources and components of these data are displayed in an open-access database.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      CI, confidence interval.

      Iron overload and hemochromatosis-associated HFE genotypes

      These data are displayed in Table 3. The estimated total number of African-American men and women ≥18 y with either HFE p.C282Y/p.C282Y or p.C282Y/p.H63D and documented IO is ∼1354 (aggregate prevalence 0.000040; 95% CI 0.000038, 0.000042). The estimated prevalence of documented IO is 12.5-fold greater in African-American men than women. The estimated total number of African-American men and women with p.C282Y/p.C282Y or p.C282Y/p.H63D and IO-related disease is ∼1057 (aggregate prevalence 0.000031; 95% CI 0.000029, 0.000033). The estimated prevalence of IO-related disease is 30.0-fold greater in African-American men than women.
      Table 3Prevalence of HFE genotypes and phenotypes in African Americans ≥18 y
      There were ∼33,932,497 self-identified black or AA ages ≥18 y (48% men, 52% women) in 2018 U.S. Census estimates.1516 CI, confidence interval.
      .
      HFE genotypes and phenotypesPrevalence [95% CI] in men (n = 16,287,599)Prevalence [95% CI] in women (n = 17,644,898)
      p.C282Y/p.C282Y
      These prevalences were derived from the data 6/34,905.11
      (prevalence 0.00017 [0.000034, 0.00031])
      2769 [554, 5049]3000 [600, 5470]
      No. with documented iron overload (36.5% men, 3.6% women)1011 [945, 1075]108 [88, 129]
      No. with iron overload-related disease (28.4% men, 1.2% women)786 [733, 847]36 [25, 48]
      p.C282Y/p.H63D
      These prevalences were derived from the data 41/33,782.11
      (prevalence 0.0012 [0.00084, 0.0016])
      19,545 [13,682, 26,060]21,174 [14,822, 28,232]
      No. with documented iron overload (1.2% men, 0% women)235 [212, 261]0 [0, 0]
      No. with iron overload-related disease (1.2% men, 0% women)235 [212, 261]0 [0, 0]
      Total no. with documented iron overload1246 [1173, 1319]108 [88, 129]
      Aggregate prevalence of documented iron overload0.000076 [0.000072, 0.000081]0.0000061 [0.0000050, 0.0000073]
      Total no. with iron overload-related disease1021 [961, 1091]36 [25, 48]
      Aggregate prevalence of iron overload-related disease0.000063 [0.000059, 0.000067]0.0000021 [0.0000014, 0.0000027]
      a There were ∼33,932,497 self-identified black or AA ages ≥18 y (48% men, 52% women) in 2018 U.S. Census estimates.

      United States Census Bureau, Population Division. Annual Estimates of the Resident Population: April 1, 2010 to July 1, 2018: 2018 Population Estimates,https://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?src=bkmk; 2018 [accessed 8.3.21 A.D.].

      United States Census Bureau, Department of Commerce. Quick Facts. United States,https://www.census.gov/quickfacts/fact/table/US/IPE120217; 2019 [accessed 8.3.21].

      CI, confidence interval.
      b These prevalences were derived from the data 6/34,905.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      c These prevalences were derived from the data 41/33,782.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.

      Discussion

      In this study, the respective prevalences of HFE p.C282Y/p.C282Y and p.C282Y/p.H63D were significantly lower in AA than EA. The occurrence of HFE p.C282Y in AA is due to European-American ancestry.
      • Acton RT
      • Wiener HW
      • Barton JC.
      Estimates of European American ancestry in African Americans using HFE p.C282Y.
      The distribution of HFE p.H63D is world-wide although the prevalence of this polymorphism is significantly lower in AA and sub-Saharan African blacks than EA or European whites.
      • Barton JC
      • Edwards CQ
      • Acton RT.
      HFE gene: Structure, function, mutations, and associated iron abnormalities.
      ,
      • Merryweather-Clarke AT
      • Pointon JJ
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      Geography of HFE C282Y and H63D mutations.
      ,
      • Merryweather-Clarke AT
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      • et al.
      Global prevalence of putative haemochromatosis mutations.
      The present estimates suggest that ∼1354 AA ≥18 y with HFE p.C282Y/p.C282Y or p.C282Y/p.H63D have IO (prevalence 0.000040) and that ∼1057 AA ≥18 y with HFE p.C282Y/p.C282Y or p.C282Y/p.H63D have IO-related disease (prevalence 0.000031). Our estimate of the prevalence of IO-related disease in African-American men with either HFE p.C282Y/p.C282Y or p.C282Y/p.H63D is 0.000063 [95% CI 0.000059, 0.000067]. The estimated prevalence of African-American men with IO-related disease was 30.0-fold greater than that of African-American women.
      We found no description of an AA with HFE p.H63D/p.H63D identified either in population screening or in a referral evaluation who had documented IO as defined herein. Proportions of referred EA and European patients in hemochromatosis case series with p.H63D/p.H63D are very low.
      • Feder JN
      • Gnirke A
      • Thomas W
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      A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
      ,
      • Barton JC
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      Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases.
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      • Kelley M
      • Joshi N
      • Xie Y
      • et al.
      Iron overload is rare in patients homozygous for the H63D mutation.
      The proportion of referred patients with p.H63D/p.H63D who have documented IO is also very low.
      • Sham RL
      • Ou CY
      • Cappuccio J
      • et al.
      Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases.
      • Brissot P
      • Moirand R
      • Jouanolle AM
      • et al.
      A genotypic study of 217 unrelated probands diagnosed as “genetic hemochromatosis” on “classical” phenotypic criteria.
      • Kelley M
      • Joshi N
      • Xie Y
      • et al.
      Iron overload is rare in patients homozygous for the H63D mutation.
      Neither novel HFE alleles nor deleterious alleles in TFR2, HAMP, and SCL40A1 were detected in referred hemochromatosis patients with p.H63D/p.H63D.
      • Aguilar-Martinez P
      • Bismuth M
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      ,
      • de Diego C
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      • et al.
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      In an analysis of 14 case-control studies of hemochromatosis, the pooled odds ratio of p.H63D/p.H63D as a contributor to hemochromatosis IO was 5.7 (95% CI 3.2, 10.1).
      • Burke W
      • Imperatore G
      • McDonnell SM
      • et al.
      Contribution of different HFE genotypes to iron overload disease: a pooled analysis.
      In a meta-analysis, p.H63D/p.H63D was significantly associated with both provisional and documented IO.
      • Neghina AM
      • Anghel A.
      Hemochromatosis genotypes and risk of iron overload - a meta-analysis.
      These latter results,
      • Burke W
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      ,
      • Neghina AM
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      derived mainly from case-control studies, cannot be extrapolated to general populations.
      HFE p.S65C (exon 2; c.193A>T; rs1800730) is the third most common pathogenic HFE coding region allele.
      • Barton JC
      • Edwards CQ
      • Acton RT.
      HFE gene: Structure, function, mutations, and associated iron abnormalities.
      ,
      • Barton JC
      • Acton RT
      • Dawkins FW
      • et al.
      Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.
      For genotypes that included p.S65C, numbers of available observations were lower in AA than EA.
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      We found no population prevalence data for AA with p.S65C and documented IO. In referred Swedish adults with p.S65C genotypes, none had IO-related disease as defined herein
      • Holmström P
      • Marmur J
      • Eggertsen G
      • et al.
      Mild iron overload in patients carrying the HFE S65C gene mutation: a retrospective study in patients with suspected iron overload and healthy controls.
      nor did any EA or AA with p.S65C detected in a population screening program have SF >1000 µ/L.
      • Beutler E
      • Felitti V
      • Gelbart T
      • et al.
      The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic.
      We selected widely acknowledged estimates of proportions of adults with documented IO and IO-related disease from large population studies of Australian whites classified by HFE genotype,
      • Gurrin LC
      • Bertalli NA
      • Dalton GW
      • et al.
      HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.
      ,
      • Allen KJ
      • Gurrin LC
      • Constantine CC
      • et al.
      Iron-overload-related disease in HFE hereditary hemochromatosis.
      although there is moderate variability of HFE hemochromatosis phenotype prevalence estimates across reports of white Europeans and EA.
      • Waalen J
      • Nordestgaard BG
      • Beutler E.
      The penetrance of hereditary hemochromatosis.
      Nonetheless, using other HFE genotype-specific phenotype prevalence estimates is unlikely to change the present estimates greatly, especially those of IO-related disease.
      Some AA with non-transfusion IO-related disease do not have common hemochromatosis-associated HFE genotypes as defined herein.
      • Labowitz DA
      • Bontreger J
      • Min AD.
      An unusual case of hemochromatosis in an African-American man: case report and review of the literature.
      ,
      • Beutler E
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      • Felitti VJ
      • et al.
      Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.
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      • et al.
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      • Monaghan KG
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      • et al.
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      • Khazaaleh S
      • et al.
      Hemochromatosis as an unusual cause of pancreatitis in an African-American female of child-bearing age.
      Sequencing all six HFE exons in two African-American men with IO revealed no mutations.
      • Beutler E
      • Gelbart T
      • West C
      • et al.
      Mutation analysis in hereditary hemochromatosis.
      The uncommon pathogenic HFE alleles p.I105T, p.G93R, p.E168Q, and p.V295E were detected in EA or white Europeans with hemochromatosis phenotypes,
      • Barton JC
      • Edwards CQ
      • Acton RT.
      HFE gene: Structure, function, mutations, and associated iron abnormalities.
      but these alleles were not detected in AA with IO, elevated TS/SF, or normal iron status.
      • Barton JC
      • Acton RT
      • Rivers CA
      • et al.
      Genotypic and phenotypic heterogeneity of African Americans with primary iron overload.
      ,
      • Barton JC
      • Lafreniere SA
      • Leiendecker-Foster C
      • et al.
      HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high-performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants.
      Other pathogenic coding region alleles of HFE
      • Barton JC
      • Edwards CQ
      • Acton RT.
      HFE gene: Structure, function, mutations, and associated iron abnormalities.
      ,
      • Wallace DF
      • Subramaniam VN.
      The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.
      are too rare to account for a substantial proportion of hemochromatosis phenotypes in Americans, regardless of ancestry. HFE intron allele IVS3 -48c>g had no effect on iron homeostasis in either AA or EA.
      • Beutler E
      • Gelbart T.
      A common intron 3 mutation (IVS3 -48c–>g) leads to misdiagnosis of the c.845G–>A (C282Y) HFE gene mutation.
      A putative iron-loading gene in black Africans who consumed traditional beer containing high concentrations of iron was not linked to the human leukocyte antigen region (chromosome 6p21.32).
      • Gordeuk V
      • Mukiibi J
      • Hasstedt SJ
      • et al.
      Iron overload in Africa. Interaction between a gene and dietary iron content.
      In three U.S. population hemochromatosis screening studies that did not use HFE allele analyses,
      • Baer DM
      • Simons JL
      • Staples RL
      • et al.
      Hemochromatosis screening in asymptomatic ambulatory men 30 years of age and older.
      • Phatak PD
      • Sham RL
      • Raubertas RF
      • et al.
      Prevalence of hereditary hemochromatosis in 16031 primary care patients.
      • Barton JC
      • Cheatwood SM
      • Key TJ
      • et al.
      Hemochromatosis detection in a health screening program at an Alabama forest products mill.
      the aggregate prevalence of non-transfusion IO-related disease in AA men consistent with the present definition was 0.0013 (3/2361 [0, 0.0027]).
      • Barton JC
      • Edwards C
      • Acton RT.
      Prevalences of hemochromatosis-associated HFE genotypes and hemochromatosis phenotypes in African Americans and European Americans based on published population and cohort studies.
      Taken together, these observations suggest that HFE p.C282Y/p.C282Y and p.C282Y/p.H63D account for a small proportion of IO-related disease in AA.
      IO-related disease in AA or black Africans due to non-HFE hemochromatosis has been reported infrequently, including hemochromatosis due to rare recessive alleles in genes that encode hemojuvelin (HJV)
      • Murugan RC
      • Lee PL
      • Kalavar MR
      • et al.
      Early age-of-onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A–>T) in an African American male of West Indies descent.
      and transferrin receptor-2 (TFR2).
      • Majore S
      • Ricerca BM
      • Radio FC
      • et al.
      Type 3 hereditary hemochromatosis in a patient from sub-Saharan Africa: is there a link between African iron overload and TFR2 dysfunction?.
      An African-American man with IO
      • Lee PL
      • Gaasterland T
      • Barton JC.
      Mild iron overload in an African American man with SLC40A1 D270V.
      and a black African woman with IO
      • Zaahl MG
      • Merryweather-Clarke AT
      • Kotze MJ
      • et al.
      Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload.
      were heterozygotes for the dominant p.D270V allele (exon 7, c.809A>T) of the SLC40A1 gene that encodes the iron exporter ferroportin. The prevalence of p.D270V in 258 AA was 0.0019 [95% CI 0.0001, 0.0124].
      • Lee PL
      • Gaasterland T
      • Barton JC.
      Mild iron overload in an African American man with SLC40A1 D270V.
      Iron
      • Perry GS
      • Byers T
      • Yip R
      • et al.
      Iron nutrition does not account for the hemoglobin differences between blacks and whites.
      ,
      • Ahluwalia N
      • Sternberg M
      • Raghavan R
      • et al.
      Race-ethnic patterns in iron intake and status in US women: findings from NHANES 2003-06.
      and alcohol
      National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism
      Alcohol Use and Alcohol Use Disorders in the United States: Main Findings from the 2001-2002.
      consumption are similar in AA and EA. Mean TS values are slightly lower in AA than EA.
      • Beutler E
      • West C.
      Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume.
      In healthy adults without liver disease, mean SF levels in AA and EA do not differ significantly.
      • Shan Y
      • Lambrecht RW
      • Bonkovsky HL.
      Association of hepatitis C virus infection with serum iron status: analysis of data from the Third National Health and Nutrition Examination Survey.
      Familial segregation of SF levels occurs in African blacks with non-transfusion IO
      • Gordeuk V
      • Mukiibi J
      • Hasstedt SJ
      • et al.
      Iron overload in Africa. Interaction between a gene and dietary iron content.
      and in whites with HFE hemochromatosis.
      • Bulaj ZJ
      • Ajioka RS
      • Phillips JD
      • et al.
      Disease-related conditions in relatives of patients with hemochromatosis.
      It is unknown whether other factors that modify occurrence of IO or IO-related disease in AA differ from those of EA with the same hemochromatosis-associated HFE genotypes.
      In the U.S., screening general adult populations for hemochromatosis with either TS/SF phenotyping or HFE genotyping is not recommended.
      • Whitlock EP
      • Garlitz BA
      • Harris EL
      • et al.
      Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force.
      • Schmitt B
      • Golub RM
      • Green R.
      Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians.
      • Adams P
      • Barton JC
      • McLaren GD
      • et al.
      Screening for iron overload: lessons from the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
      In a clinical setting, it is prudent to perform TS/SF phenotyping in persons with liver disease or other manifestations suggestive of or consistent with IO, and to perform HFE genotyping in persons with TS/SF phenotypes consistent with hemochromatosis.
      • Bacon BR
      • Adams PC
      • Kowdley KV
      • et al.
      Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases.
      It is also recommended that first-degree relatives of persons diagnosed to have HFE hemochromatosis undergo TS/SF phenotyping and HFE genotyping.
      • Bacon BR
      • Adams PC
      • Kowdley KV
      • et al.
      Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases.
      There is no evidence that detecting HFE alleles has disease-identification value other than to reveal IO risk.
      A strength of the present report is the relatively great numbers of African-American study participants from which we tabulated allele prevalence data, permitting estimates of genotype prevalences with relatively narrow CI. An uncertainty of this study is the self-reported race/ethnicity of the present subjects. Some subjects may have reported their race/ethnicity according to social identity or preference, not ancestry or physical attributes. We cannot exclude the possibility that some of the present subjects classified as AA are descendants of enslaved West African blacks who were transported to the Caribbean or Brazil and later came to the present region of the U.S. Measuring hepcidin levels, assessing possible genetic or environmental modifiers of hemochromatosis-associated HFE genotypes, or evaluating p.C282Y heterozygosity as a possible modifier of non-HFE iron overload
      • Barton JC
      • Acton RT
      • Rivers CA
      • et al.
      Genotypic and phenotypic heterogeneity of African Americans with primary iron overload.
      was beyond the scope of this study.

      Conclusions

      We conclude that ∼1/25,061 AA >18 y have a hemochromatosis-associated HFE genotype and IO and that ∼1/31,921 AA >18 y have a hemochromatosis-associated HFE genotype and IO-related disease.

      Declaration of Competing Interest

      None of the authors has a conflict of interest to report.

      Source of funding statement

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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