An Update on Iron Homeostasis: Make New Friends, but Keep the Old

Roy, Cindy N.

doi:10.1097/maj.0000000000000190

Cited by 9 publications

(6 citation statements)

References 102 publications

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“…Our observations suggest that loss of GNPAT expression or single‐nucleotide variants, which affect GNPAT expression/activity, affect HAMP expression and that GNPAT is a potential genetic modifier of hemochromatosis iron phenotypes. Although hepcidin is down‐regulated in HFE C282Y homozygotes, hepcidin expression is lower in C282Y homozygotes who also have HAMP , HJV , or TFR2 mutations, implying that further down‐regulation is possible. Thus, GNPAT variants, such as GNPAT p.D519G, identified in the current study could cause further down‐regulation of hepcidin.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

McLaren¹,

Emond²,

Subramaniam

et al. 2015

Hepatology

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To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n=22; cases) or with normal or mildly increased iron stores (n=13; controls). The 35 participants, residents of the U.S., Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (p = 3×10−6, p=0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of 22 participants with severe iron overload had GNPAT polymorphism p.D519G (rs11558492) (15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed siRNA-based knockdown of GNPAT in the human liver-derived cell line HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the mRNA encoding the iron regulatory hormone hepcidin. Conclusion: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload

McLaren¹,

Emond²,

Subramaniam

et al. 2015

Hepatology

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“…When confronted with infection and inflammation the human host reallocates its iron reservoirs in an effort to deprive invading pathogens of iron. The human protein hepcidin—a rheostat of systemic iron homeostasis—signals the body to decrease absorption of iron in the proximal duodenum and orchestrates the movement of iron from serum into storage within the liver and macrophages (Roy, 2013). As a result of reduced serum iron, erythropoiesis—a process exquisitely sensitive to iron levels—slows in the face of infection as well as inflammation.…”

Section: Biological Importance Of Ironmentioning

confidence: 99%

Influence of host iron status on Plasmodium falciparum infection

2014

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Iron deficiency affects one quarter of the world's population and causes significant morbidity, including detrimental effects on immune function and cognitive development. Accordingly, the World Health Organization (WHO) recommends routine iron supplementation in children and adults in areas with a high prevalence of iron deficiency. However, a large body of clinical and epidemiological evidence has accumulated which clearly demonstrates that host iron deficiency is protective against falciparum malaria and that host iron supplementation may increase the risk of malaria. Although many effective antimalarial treatments and preventive measures are available, malaria remains a significant public health problem, in part because the mechanisms of malaria pathogenesis remain obscured by the complexity of the relationships that exist between parasite virulence factors, host susceptibility traits, and the immune responses that modulate disease. Here we review (i) the clinical and epidemiological data that describes the relationship between host iron status and malaria infection and (ii) the current understanding of the biological basis for these clinical and epidemiological observations.

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“…These intricate mechanisms confer protection against iron overdose, and their disruption (e.g. in hereditary hemochromatosis) can cause widespread organ damage [18]. As an acute phase reactant, hepcidin expression also increases in the presence of inflammation [16].…”

Section: Key Pointsmentioning

confidence: 99%