Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans

doi:10.1016/S1079-9796(03)00165-7

Blood Cells, Molecules, and Diseases

Volume 31, Issue 3, November–December 2003, Pages 305-309

https://doi.org/10.1016/S1079-9796(03)00165-7 Get rights and content

Abstract

We find that in the Black American population average ferritin levels are higher than those in Whites, both among men and women. African-Americans have an increased prevalence of iron storage disease characterized by prominent iron deposition in macrophages of the liver and other organs. The iron distribution in patients with mutations of the ferroportin gene is similar. A c.744 G→T (Gln 248 His) mutation was detected among African-Americans at polymorphic frequencies. This variant is associated with increased ferritin levels in African-Americans and may play a role in their propensity to develop iron overload.

Introduction

Severe iron overload in South African Bantu has been appreciated for more than half a century [1]. However, the relative roles that diet, other environmental factors, and a genetic predisposition play have been less clear. That genetic factors are operative was suggested by the studies of Gordeuk et al. in southern and central Africans [2] and by the increased prevalence and familial occurrence of iron overload among African-Americans [3], [4].

The most common form of hemochromatosis among Europeans is associated with mutations of the HLA-linked gene HFE. This form of hemochromatosis is characterized by accumulation of large amounts of iron in liver parenchymal cells and, in the fully developed form, hepatic cirrhosis, diabetes mellitus, and cardiomyopathy. African iron overload is not HLA-linked [2] and is therefore not related to mutations of the HFE gene [4]. Although total body iron and serum ferritin levels are increased in both HFE hemochromatosis and African iron overload, excess iron in African iron overload is located predominantly in macrophages, whereas in HFE hemochromatosis macrophage iron deposits are decreased or absent [2]. In HFE hemochromatosis the plasma transferrin saturation is almost invariably increased, while elevated values are observed less frequently in African iron overload [2].

An autosomal dominant form of iron overload has been documented [3], [4], [5]. Subsequently, some cases of autosomal dominant iron overload were found to be due to mutations of ferroportin (ferroportin1; FPN1; MTP1; Ireg1; SLC11A3; SCL40A1) [6], [7], [8], [9], [10], [11]. These cases are characterized by prominent macrophage localization of the stored iron. We therefore undertook a survey of African-American subjects to determine whether mutations of this gene may be responsible, at least in part, for the iron overload observed in African-Americans and presumably also in the South African Bantu population.

Section snippets

Materials and methods

DNA samples were obtained with informed consent from three sources: (a) African-American subjects studied for possible iron overload as reported previously [12]; (b) African-American subjects in Alabama attending the Southern Iron Disorders Center, Birmingham, Alabama; and (c) the Coriell Institute of Medical Research (http://locus.umdnj.edu/nigms/products/pdr.html). All samples from Kaiser Permanente and Alabama were typed for HFE C282Y and H63D mutations, and studies were limited to

Ethnic differences in ferritin levels and transferrin saturation

Table 1 summarizes the mean ferritin and transferrin saturation values for the white and African-American among males and females. Ferritin levels of African-American subjects were significantly higher than those of the white subjects among both males and females. On the other hand, transferrin saturations were significantly lower among African-American subjects. The differences were maintained among males when stratified by age (≥56 years vs <56 years) (Table 2). Ferritin values did not

Discussion

It has been known since the 1920s [1] that Africans have a tendency to develop iron storage disease. More recently, data have been presented that suggest that this propensity has, at least in part, a genetic basis [2] and that it extends to people of African origin living in the United States [3], [4]. The nature of the genetic changes predisposing to iron overload in the African and African-American population remains to be elucidated fully. Because ferroportin mutations are associated with

Acknowledgements

This is Manuscript No. 15856-MEM. This study was supported by National Institutes of Health Grants DK53505-04 and RR00833 and the Stein Endowment Fund (E.B.) and by NIGMS U01GM61390 and HFSP RGY0328 (C.V.).

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Iron disorders of the liver are best understood in the context of normal iron metabolism, so the biology of iron metabolism and homeostasis is reviewed. Mutations that lead to dysregulation of normal iron homeostasis are the basis for genetic iron overload. These mutations and their clinical and histological manifestations are examined, with a focus on information relevant to diagnostic surgical pathology. Secondary iron is also discussed, including its many causes and the histological manifestations.
HFE hemochromatosis in African Americans: Prevalence estimates of iron overload and iron overload-related disease
2023, American Journal of the Medical Sciences
Little is known about the prevalence of HFE (homeostatic iron regulator) hemochromatosis in African Americans (AA).
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.
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.
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.
Ferroportin Q248H mutation was not found to be protective against malaria and anemia in children under 5 years living in South Kivu/Democratic Republic of Congo, an endemic area of Plasmodium infection
2022, Heliyon
Ferroportin (FPN) is known as an iron exporter and its effect on RBC iron could therefore hamper the growth of malaria parasites, since parasites are in need of iron. The aim of this study was to examine the prevalence of FPN Q248H in South Kivu/DRC and to evaluate its role in Plasmodium infected children and to explore its relationship with anemia.
We conducted a cross-sectional study in the health zone of Miti Murhesa in South Kivu/DRC. 1088 children aged under five years were included. The FPN Q248H mutation was analyzed by PCR (N = 1071). Allele frequency was calculated based on Hardy-Weinberg equation. Plasmodium infection was assessed by LAMP malaria assay (N = 1057). Statistical analysis was done using Medcalc® software. P-values < 0.05 were considered significant.
We found 11.4% FPN Q248H mutation. T allele frequency was estimated to be 0.0588 ± 0.0052. No significant differences for frequencies of anemia and malaria were observed between FPN Q248H mutation and FPN wild type. However, Plasmodium infected carriers of the FPN Q248H mutation had lower hemoglobin values than wild type children.
Even though FPN Q248H mutation is associated with lower hemoglobin values in Plasmodium infected children, it was not found to be protective against malaria and anemia in children under 5 years living in malaria endemic area of South Kivu/Democratic Republic of Congo.
Ethnic Differences in Iron Status
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Iron is unique among all minerals in that humans have no regulatable excretory pathway to eliminate excess iron after it is absorbed. Iron deficiency anemia occurs when absorbed iron is not sufficient to meet body iron demands, whereas iron overload and subsequent deposition of iron in key organs occur when absorbed iron exceeds body iron demands. Over time, iron accumulation in the body can increase risk of chronic diseases, including cirrhosis, diabetes, and heart failure. To date, only ∼30% of the interindividual variability in iron absorption can be captured by iron status biomarkers or iron regulatory hormones. Much of the regulation of iron absorption may be under genetic control, but these pathways have yet to be fully elucidated. Genome-wide and candidate gene association studies have identified several genetic variants that are associated with variations in iron status, but the majority of these data were generated in European populations. The purpose of this review is to summarize genetic variants that have been associated with alterations in iron status and to highlight the influence of ethnicity on the risk of iron deficiency or overload. Using extant data in the literature, linear mixed-effects models were constructed to explore ethnic differences in iron status biomarkers. This approach found that East Asians had significantly higher concentrations of iron status indicators (serum ferritin, transferrin saturation, and hemoglobin) than Europeans, African Americans, or South Asians. African Americans exhibited significantly lower hemoglobin concentrations compared with other ethnic groups. Further studies of the genetic basis for ethnic differences in iron metabolism and on how it affects disease susceptibility among different ethnic groups are needed to inform population-specific recommendations and personalized nutrition interventions for iron-related disorders.
Iron Metabolism and Related Disorders
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Iron is an essential element for numerous fundamental biological processes, including erythropoiesis; however, in large quantities and when unbound, iron can be highly toxic to cells. Much of iron metabolism involves maintaining a delicate balance between sequestered and available iron by regulating iron movement between compartments where iron can be absorbed, recycled, and stored. A wide spectrum of clinical disorders result from mutations in gene products with key roles in cellular and systemic iron regulation. Mutations in the gene products that encode the master iron regulatory hormone hepcidin or its receptor ferroportin lead to several hereditary forms of hemochromatosis with juvenile or adult onset. Genetic defects that restrict iron availability to erythroid precursors underlie several clinically-distinct forms of microcytic anemia that are also characterized by dysregulated systemic iron balance, including iron-refractory iron deficiency anemia, DMT1 mutation-related hypochromic microcytic anemia, and congenital atransferrinemia. A variety of other inherited conditions, including hereditary hyperferritinemia-cataract syndrome, neuroferritinopathy, aceruloplasminemia, Friedreich ataxia, and X-linked sideroblastic anemia with ataxia, also result from genetic defects that disrupt iron homeostasis at the local or systemic level. Furthermore, several genetic forms of neurodegeneration with brain iron accumulation have been described for which the relationship of the underlying mutated gene product to iron metabolism remains to be elucidated. In this chapter, we review the clinical features, molecular genetics, pathophysiology, diagnosis, and management of the major genetic disorders of iron metabolism.
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Regular articleFerroportin 1 (SCL40A1) variant associated with iron overload in African-Americans

Abstract

Introduction

Section snippets

Materials and methods

Ethnic differences in ferritin levels and transferrin saturation

Discussion

Acknowledgements

Am. J. Med

Am. J. Med

Mol. Genet. Metab

Blood

Blood Cells Mol. Dis

Blood Cells Mol. Dis

J. Nutr

Blood

Haemosiderosis and haemochromatosis in South African natives with a comment on the etiology of haemochromatosis, M.D. Thesis

Iron overload in Africa. Interaction between a gene and dietary iron content

N. Engl. J. Med

Regular article
Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans