Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

doi:10.1016/j.bcmd.2006.12.002

Blood Cells, Molecules, and Diseases

Volume 38, Issue 3, May–June 2007, Pages 247-252

https://doi.org/10.1016/j.bcmd.2006.12.002 Get rights and content

Abstract

The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥ 300 μg/L in men and ≥ 200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF.

Introduction

The ferroportin (FPN1) Q248H polymorphism (cDNA 744 G→T [Gln248His, Q248H]) occurs in sub-Saharan African Natives and in African Americans (AA) with and without iron overload [1], [2], [3]. However, the possible role of Q248H in the causation of increased serum ferritin concentration (SF) or iron overload in sub-Saharan African Natives or AA is incompletely defined. Among 22 southern African first-degree family members, 10 of whom were Q248H heterozygotes, Q248H was associated with a trend of higher SF to aspartate aminotransferase ratios [3]. In 278 AA males and 293 AA females from a southern California screening program who lacked HFE C282Y, the mean SF of 26 Q248H heterozygotes did not differ significantly from that of wild-type homozygotes [2]. When the distribution of genotypes among these subjects was stratified to SF of more or less than 500 μg/L in men, and more or less than 350 μg/L in women, a χ² test for trend was highly significant [2].

The HEIRS Study is an on-going investigation to evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal and societal impact of iron overload and hemochromatosis in a multi-center, multi-ethnic, primary care-based sample of 100,000 adults ≥ 25 years of age [4]. All participants were screened by performing serum biochemical tests of iron status (serum transferrin saturation, SF) and genotyping for the common C282Y and H63D mutations of the hemochromatosis gene (HFE). We hypothesized that the frequency of the FPN1 Q248H polymorphism in AA HEIRS Study participants with elevated SF is higher than that in AA participants with normal SF. Therefore, we selected AA participants who did not have HFE C282Y or H63D, and compared the prevalence of Q248H in participants with elevated SF with that in participants whose SF was normal. The possible association of Q248H with elevated SF and with iron overload is discussed.

Section snippets

Recruitment of participants

The design of the HEIRS Study has been reported in detail [4]. All AA HEIRS Study participants were recruited from public and private primary care settings at these HEIRS Field Centers: Howard University (Washington, DC), University of Alabama at Birmingham (Birmingham, AL), University of California, Irvine (Irvine, CA), and Kaiser Permanente (Portland, OR). All participants were ≥ 25 years old and gave informed consent.

HFE genotype analyses and serum ferritin measurements

HFE C282Y and H63D were assessed in DNA from the buffy coat of whole-blood

Characteristics of participants

The proportions of women in case and control groups were greater than the proportions of men in these respective groups (Table 1); this is consistent with the greater proportion of women than men who participated in the HEIRS Study [5]. The mean ages of men and women in case and control subgroups did not differ significantly (P = 0.859). The percentages of women in case and control subgroups who reported having arthritis were significantly greater than the percentages of men in the respective

Discussion

In the present study, the frequency of FPN1 Q248H was greater in AA men with elevated SF than in those with normal SF. This is consistent with our hypothesis that SF is positively associated with Q248H, and with previous reports [2], [3]. Further, the occurrence of Q248H in AA could partly explain the higher mean SF levels typically observed in AA than in whites [1], [2], [3]. However, a corresponding difference in Q248H frequency between women with elevated SF and those with normal SF was not

Acknowledgments

The HEIRS Study was initiated and funded by the National Heart, Lung, and Blood Institute, in conjunction with the National Human Genome Research Institute. The Study is supported by contracts N01-HC05185 (University of Minnesota); N01-HC05186, N01-CM-07003-74, and Minority CCOP (Howard University); N01-HC05188 (University of Alabama at Birmingham); N01-C05189 (Kaiser Permanente Center for Health Research); N01-HC05190 (University of California, Irvine); N01-HC05191 (London Health Sciences

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Prevalences of human herpesvirus-8 (HHV-8) infection and diabetes mellitus are very common in certain parts of Africa, containing iron-rich soils. We hypothesized that some genetic factors could have a link with susceptibility to HHV-8 infection. We focused on ferroportin Q248H mutation (rs11568350), transferrin (TF) polymorphism and fructosamine-3 kinase (FN3K) 900C/G polymorphism (rs1056534). The study population consisted of 210 type 2 diabetic adults and 125 healthy controls recruited in Bukavu (South Kivu). In the whole study population (diabetics + healthy controls), ferroportin Q248H mutation was detected in 47 subjects (14.0%) with 43 heterozygotes and 4 homozygotes. TF phenotype frequencies were 88.1% (CC), 10.4% (CD) and 1.5% (BC). Genotype frequencies of FN3K 900C/G polymorphism were respectively 9,3% (CC), 43.3% (GC) and 47.4% (GG). Prevalence of HHV8-infection in the study population was 77.3%. HHV-8 infection rate and HHV-8 IgG antibody titer were significantly higher in diabetics then in controls (p < 0.0001). Significant differences were observed in HHV-8 infection rate and in HHV-8 IgG antibody titer according to FN3K rs1056534 (p < 0.05 and p < 0.05, respectively) and TF polymorphism (p < 0.05 and p = 0.005, respectively). No significant differences in HHV-8 infection rate and in HHV-8 IgG antibody titer were observed in the ferroportin Q248H mutation carriers (rs11568350) in comparison with ferroportin wild type. In a multiple regression analysis, FN3K rs1056534, TF polymorphism and presence of diabetes mellitus were predictors for HHV-8 infection. In contrast to these findings, ferroportin Q248H mutation (rs11568350) did not influence the susceptibility for an HHV-8 infection in sub-Saharan Africans.
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In principle, some mutations could cause both decreased iron export and partial resistance to hepcidin, and this could help explain the variable iron-loading phenotypes in patients with the same mutation. The ferroportin variant Q248H is common (a few percent) in populations of African ancestry and has been weakly associated with increased serum ferritin (Gordeuk et al., 2003; Kasvosve et al., 2015; Rivers et al., 2007). The polymorphism may confer a somewhat decreased sensitivity of ferroportin to hepcidin, perhaps because of its proximity to cytoplasmic ubiquitination sites involved in hepcidin-induced ferroportin endocytosis (Nekhai et al., 2013).
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The effect of the ferroportin Q248H mutation on iron homeostasis is inconclusive [8,9]. Studies on the effect of ferroportin Q248H mutation have been conducted on subjects with increased iron stores or hyperferritinemia [6,10–13]. In one study, ferroportin Q248H polymorphism was reported to be associated with increased iron stores in African-Americans [13].
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Ferroportin Q248H mutation was identified in 30 individuals (17.2%) (one homozygote, 29 heterozygotes) and was absent in 144 individuals (82.8%), with Q248H allele frequency of 8.9%. In males, SF was significantly higher in ferroportin Q248H heterozygotes compared to wild types, p = 0.029, but the relationship between ferroportin Q248H mutation and iron stores was blunted in females.
Our study of healthy adults provides further evidence that ferroportin Q248H mutation affects SF concentration in Africans.
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Since HCC occurs almost exclusively in HH patients who have developed cirrhosis, there is limited evidence of a direct role for excess iron in carcinogenesis; instead, cirrhosis may provide the link for progression to HCC. Increased risk of developing HCC also exists with a disorder called African iron overload (AIO), which most probably arises through interaction between environmental factors (e.g. consumption of iron-rich beverages brewed in non-galvanized steel drums) and potential genetic factors [29,30]. Several studies and a large meta-analysis investigating the risk of non-hepatic cancers in patients with HH or with HH-predisposing genotypes have provided conflicting results [27,31–36] considerable.
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Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Abstract

Introduction

Section snippets

Recruitment of participants

HFE genotype analyses and serum ferritin measurements

Characteristics of participants

Discussion

Acknowledgments

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Blood Cells, Mol. Dis.

Am. J. Med. Sci.

Blood Cells, Mol. Dis.

Clin. Immunol.

Neurosci. Lett.

Blood Cells, Mol. Dis.

Int. J. Biochem. Cell Biol.

Blood Cells, Mol. Dis.

Am. J. Clin. Nutr.

Am. J. Med.