Ferritin

Background

Ferritin is a protein that plays a vital role in storing iron within cells, making it crucial for maintaining the body’s iron balance. It acts as a primary iron storage protein, preventing both iron deficiency and iron overload. The of serum ferritin, the small amount of ferritin released into the bloodstream, is widely recognized as a key indicator of the body’s overall iron stores.^[1]

Biological Basis

Iron is an essential mineral necessary for numerous biological processes, including oxygen transport in red blood cells (as part of hemoglobin), energy production, and various enzymatic reactions. However, free iron can be toxic due to its ability to generate harmful reactive oxygen species. To manage this, the body tightly regulates iron storage and release. Ferritin forms a spherical protein shell that can safely store thousands of iron atoms in a non-toxic, soluble form, making them readily available when needed. The concentration of ferritin in the serum generally reflects the amount of iron stored in tissues.^{[1], [2]}

Clinical Relevance

Ferritin levels are routinely assessed in clinical practice to diagnose and monitor a range of iron-related health conditions. Abnormally low ferritin levels typically indicate iron deficiency, which can progress to iron deficiency anemia, leading to symptoms such as fatigue, weakness, and impaired cognitive function. Conversely, elevated ferritin levels can signal iron overload conditions, such as hemochromatosis, where excessive iron accumulation can damage vital organs like the liver, heart, and pancreas.^[3]It is also important to note that ferritin can act as an acute-phase reactant, meaning its levels can be elevated due to inflammation, infection, or liver disease, even in the absence of true iron overload. Genetic variations in genes such asHFEare known to influence iron metabolism and are associated with hemochromatosis, which often presents with high ferritin levels.^[3] Other genes, including TMPRSS6 and TFR2, also contribute to the complex regulation of iron and can impact ferritin levels and other iron parameters.^[3]

Social Importance

Iron deficiency is a global public health concern, affecting billions worldwide and particularly prevalent among women and children. It has significant impacts on development, productivity, and overall well-being. Conversely, iron overload, though less common, can lead to severe and potentially life-threatening health complications if not properly diagnosed and managed. Accurate assessment of ferritin levels enables healthcare professionals to identify individuals at risk, guide appropriate nutritional interventions, and manage chronic diseases. Understanding the genetic factors that influence ferritin levels can further enhance personalized diagnostic and therapeutic strategies, contributing to improved public health outcomes and quality of life.

Methodological Heterogeneity and Variability

Research into ferritin levels faces limitations due to the variability in methodologies across different studies. For instance, serum ferritin was quantified using diverse immunoassay platforms, such as electrochemiluminescence immunoassay (Roche) in some cohorts and microparticle enzyme immunoassay (Abbott) in others.^[1]Such inter-assay differences can introduce technical variability and potential biases, complicating the direct comparison of ferritin values and potentially impacting the robustness of meta-analyses. Similarly, genotyping was performed on various platforms, including Affymetrix and Illumina arrays, which, despite subsequent imputation, could contribute to subtle differences in genetic data quality and consistency across cohorts.^[1] These technical inconsistencies require careful consideration as they may influence the precision of observed associations and the overall interpretability of the findings.

Confounding Factors and Phenotypic Complexity

The interpretation of ferritin levels is inherently complex due to the influence of various physiological and environmental confounding factors. Serum ferritin is notably affected by menopausal status and the specific time of day blood samples are collected.^[4] Studies that do not standardize blood collection times or include individuals across different menopausal states may introduce significant confounding, making it challenging to isolate true genetic effects.^[4]For example, some cohorts included subjects whose bloods were collected at varying times throughout the day, and some participants had reached menopause, which can obscure genetic associations with ferritin or lead to spurious findings if these variables are not adequately controlled for in the analyses.^[4]This highlights the need for rigorous control of non-genetic factors to accurately assess the underlying genetic contributions to ferritin variation.

Generalizability and Statistical Constraints

The generalizability of findings concerning ferritin levels may be constrained by the specific demographic and genetic characteristics of the studied populations. For example, some cohorts included distinct populations, such as an isolated island population, which may not be representative of broader ancestral groups.^[1]This specificity can limit the extrapolation of observed genetic associations to more diverse populations, necessitating replication in varied ancestries. Furthermore, while meta-analyses included a substantial number of individuals (e.g., 6592 for ferritin), the statistical power for detecting variants with very small effect sizes might still be limited.^[1]This can lead to effect-size inflation for initially reported associations or contribute to remaining knowledge gaps, especially if complex genetic architectures or gene-environment interactions are not fully captured by the assumption of additive genetic effects.^[1]

Variants

Genetic variations play a crucial role in regulating iron metabolism and influencing circulating ferritin levels, which serve as a key indicator of the body’s iron stores. Variants in genes such asHFE and TMPRSS6 are particularly well-characterized for their direct involvement in iron homeostasis. The HFEgene encodes a protein that interacts with the transferrin receptor, playing a central role in sensing systemic iron levels and regulating the production of hepcidin, the master hormone of iron metabolism.^[3] The variant rs1799945 (also known as C282Y) in HFE is strongly associated with elevated serum iron levels and is a primary cause of hereditary hemochromatosis, a condition characterized by excessive iron accumulation.^[3] Another HFE variant, rs1800562 (H63D), is also linked to hemochromatosis and correlates with other genetic signals associated with ferritin, contributing to the genetic variability in iron status.^[3] Similarly, the TMPRSS6gene encodes matriptase-2, a transmembrane serine protease that negatively regulates hepcidin production. Variants withinTMPRSS6, such as rs855791 , can influence hepcidin levels, thereby modulating dietary iron absorption and ultimately affecting ferritin concentrations . For instance,rs4820268 in TMPRSS6has been associated with iron levels, soluble transferrin receptor (sTfR), and the sTfR-ferritin index, highlighting the gene’s broad impact on iron status.^[3] Common variants in TMPRSS6are known to be associated with overall iron status, erythrocyte volume, and hemoglobin levels.^[4]Beyond these primary iron regulators, other genes involved in diverse cellular processes also contribute to the complex regulation of ferritin. Variants inDUOX2, which codes for Dual Oxidase 2, a protein essential for thyroid hormone synthesis, may indirectly affect iron metabolism.DUOX2 variants like rs57659670 , rs56833067 , and rs73406330 could alter cellular redox balance or thyroid function, both of which can influence iron handling and ferritin levels, as iron is intimately linked to oxidative stress and metabolic health . TheEGLN3 gene, also known as PHD3, is a prolyl hydroxylase involved in the hypoxia-inducible factor (HIF) pathway, a critical system for sensing oxygen levels and regulating genes involved in erythropoiesis and iron metabolism . The variant rs996347 in EGLN3may alter HIF pathway activity, thereby affecting iron absorption and storage, which directly impacts serum ferritin levels . Furthermore, theF5 gene, encoding Coagulation Factor V, plays a vital role in blood coagulation. The rs6025 variant, commonly known as Factor V Leiden, is associated with an increased risk of thrombosis. While primarily impacting blood clotting, chronic inflammation or thrombotic states can influence iron metabolism, as ferritin itself is an acute phase reactant, meaning its levels can rise in response to inflammation .

Other genetic variations contribute to the intricate landscape of ferritin regulation through various mechanisms. TheSLC40A1 gene, which encodes ferroportin, is the sole known iron exporter protein, making its function critical for systemic iron balance . Variants such as rs12693541 and rs744653 in SLC40A1can directly impact ferroportin’s activity, altering the release of iron from cells into circulation and consequently affecting ferritin levels, which reflect the body’s stored iron . Genes likeH2BC4, a histone component, and KDM3AP1, a pseudogene related to histone demethylation, could indirectly affect gene expression through epigenetic mechanisms . Such broad regulatory impacts might influence the expression of genes involved in iron homeostasis, thereby having a downstream effect on ferritin. Similarly,TXNL4B (rs217181 ) and DHX38 (rs9302635 ) are involved in RNA splicing, and variants in these genes could alter protein production or stability for numerous cellular pathways, potentially including those related to iron metabolism . The HPR gene, related to haptoglobin, might indirectly affect iron recycling from heme. Furthermore, variants in RNF43, a ubiquitin ligase involved in Wnt signaling, and in the TSPOAP1-AS1 long non-coding RNA (rs34523089 , rs263251 ), as well as the WNT4-MIR4418 intergenic variant rs75965181 , may exert their influence through complex gene regulatory networks or signaling pathways that, while not directly regulating iron, can impact cellular function and inflammatory responses, ultimately modulating ferritin levels .

Key Variants

RS ID	Gene	Related Traits
rs57659670 rs56833067 rs73406330	DUOX2	total iron binding capacity ferritin serum iron amount transferrin saturation coronary artery disease
rs1800562 rs1799945	H2BC4, HFE	ferritin iron biomarker , transferrin saturation iron biomarker , serum iron amount iron biomarker , transferrin hematocrit
rs217181	HPR - TXNL4B	coronary artery calcification FADD/MGLL protein level ratio in blood FIS1/MGLL protein level ratio in blood CXCL3/MGLL protein level ratio in blood ENO2/MGLL protein level ratio in blood
rs9302635	DHX38	urate blood protein amount phospholipids:totallipids ratio, high density lipoprotein cholesterol triglycerides:total lipids ratio, blood VLDL cholesterol amount ferritin
rs12693541 rs744653	KDM3AP1 - SLC40A1	ferritin total iron binding capacity
rs34523089 rs2632513	RNF43, TSPOAP1-AS1	erythrocyte volume blood protein amount mean corpuscular hemoglobin hematocrit hemoglobin
rs996347	EGLN3	ferritin hepcidin
rs6025	F5	venous thromboembolism Ischemic stroke, venous thromboembolism, stroke, Abnormal thrombosis, deep vein thrombosis, pulmonary embolism inflammatory bowel disease peripheral arterial disease peripheral vascular disease
rs855791	TMPRSS6	mean corpuscular hemoglobin ferritin iron biomarker , transferrin saturation iron biomarker , serum iron amount iron biomarker , transferrin
rs75965181	WNT4 - MIR4418	ferritin hepcidin

Genetic Predisposition to Ferritin Levels

Serum ferritin levels, a key indicator of body iron storage, are significantly influenced by an individual’s genetic makeup. Common genetic variants contribute to the physiological regulation and variability observed in ferritin concentrations. For instance, an association has been identified in theSLC17A1 gene (rs17342717 ) that directly correlates with ferritin levels.^[3] This particular genetic signal is understood to reflect an association with the HFE gene, specifically correlating with the HFE variant rs1800562 , which is well-known for its role in hemochromatosis.^[3]While these individual replicated single nucleotide polymorphisms (SNPs) explain a modest phenotypic variance for ferritin, typically between 0.9 and 1%, they highlight the polygenic nature of ferritin regulation.^[3]

Genetic Regulation of Systemic Iron Homeostasis

Beyond direct associations with ferritin, numerous genetic factors profoundly impact systemic iron homeostasis, thereby indirectly but critically influencing ferritin levels. Genes such asTFR2(Type 2 Transferrin Receptor),TMPRSS6(Transmembrane Protease, Serine 6), andHFE (Hemochromatosis) play pivotal roles in iron absorption, transport, and cellular sensing. For example, a common variant in the TFR2 gene (rs7385804 ) is implicated in the physiological regulation of serum iron levels, and its function is crucial for proper hepcidin activation.^[3] The HFE gene, with variants like rs1799945 , also demonstrates a confirmed association with serum iron levels, underscoring its broad impact on iron metabolism.^[3] The intricate interplay between these genes governs the body’s iron balance. Specifically, the HFE-TFR2complex is instrumental in activating hepcidin transcription, a master regulator of systemic iron.^[3] Dysregulation of this pathway, often due to genetic variants, can lead to conditions of iron overload or deficiency. For instance, targeted deletion of the TFR2gene in mice results in iron overload coupled with low basal hepcidin levels, a phenomenon also observed in humans, directly impacting the amount of iron stored and subsequently, circulating ferritin.^[3]

Ferritin’s Role in Iron Homeostasis

Ferritin is a crucial protein involved in iron storage within cells, acting as a cellular iron buffer. It sequesters excess iron in a non-toxic, bioavailable form, thereby protecting cells from the damaging effects of free iron radicals.^[5]Serum ferritin levels serve as a primary indicator of the body’s overall iron stores and reflect the erythropoietic need for iron.^[1]This makes serum ferritin a valuable diagnostic marker for assessing an individual’s iron status.^[6]The concentration of ferritin in the blood is generally proportional to the total amount of iron stored in various tissues, particularly in the bone marrow.^[6]When iron levels are high, ferritin synthesis increases, leading to more iron storage; conversely, when iron levels are low, ferritin releases stored iron for critical cellular functions. This dynamic regulation ensures systemic iron balance, which is vital for numerous biological processes, including oxygen transport, DNA synthesis, and energy production.^[5]

Iron Metabolism and Associated Biomarkers

Iron metabolism is a complex process involving multiple key biomolecules that regulate its absorption, transport, storage, and utilization throughout the body. Beyond ferritin, other critical proteins like transferrin, which transports iron in the bloodstream, and its receptor, soluble transferrin receptor (sTfR), play integral roles.^[1]Transferrin saturation (TfS), total iron-binding capacity (TIBC), and unsaturated iron-binding capacity (UIBC) are additional quantitative measures used to assess different aspects of iron status.^[2]These biomolecules and their interactions are part of a sophisticated regulatory network ensuring that iron is available where needed while preventing its accumulation to toxic levels. For example, in states of iron deficiency, serum iron may be normal, but total iron-binding capacity can be elevated as the body attempts to maximize iron uptake.^[7] Measuring these various parameters together provides a comprehensive picture of systemic iron dynamics, highlighting the interconnectedness of these metabolic processes at the tissue and organ level.

Genetic Regulation of Iron Stores

Genetic mechanisms significantly influence an individual’s iron stores and metabolism. Polymorphisms in genes such as HFE, specifically the C282Y and H63D variants, are known to impact iron accumulation and contribute to variations in iron stores within the population.^[8] These genetic variations can alter the function of proteins involved in iron sensing and regulation, leading to disruptions in iron homeostasis.

Furthermore, polymorphisms in the transferrin gene itself can affect iron metabolism, influencing how efficiently iron is transported throughout the body.^[9] Recent genome-wide association studies have identified novel genetic loci, such as the proprotein convertase PCSK7gene locus, that are associated with levels of iron-related biomarkers like soluble transferrin receptor, indicating a broader genetic landscape governing iron regulation.^[1] These genetic insights underscore the polygenic nature of iron metabolism and its susceptibility to inherited variations.

Pathophysiological Implications of Ferritin Levels

Disruptions in iron homeostasis, often reflected by abnormal ferritin levels, are central to several pathophysiological processes. Low serum ferritin is a hallmark of iron deficiency, a common nutritional disorder that can lead to anemia and impaired physiological functions.^[2]Conversely, elevated ferritin levels can indicate iron overload, a condition seen in disorders like hemochromatosis, where excessive iron accumulation can cause organ damage.^[10]The precise monitoring of ferritin, alongside other iron biomarkers, is crucial for diagnosing and managing these conditions. Early detection of iron imbalances, whether deficiency or overload, allows for timely interventions that can prevent severe health consequences and maintain overall health.^[5] These measurements provide essential insights into homeostatic disruptions and guide therapeutic strategies to restore proper iron balance within the body.

Systemic Iron Homeostasis and Ferritin Dynamics

Ferritin serves as a crucial indicator for the body’s iron storage levels and the erythropoietic demand for iron.^{[1], [6], [11], [12]} The maintenance of systemic iron balance, or homeostasis, is a complex process primarily achieved through meticulous control of intestinal iron absorption and the efficient recycling of heme iron from senescent red blood cells by macrophages.^[3] This intricate system-level integration ensures that iron is adequately supplied for vital physiological functions while preventing both iron deficiency and potentially toxic iron overload. The dynamic regulation of cellular and systemic iron acquisition is critical for overall health.

Hormonal and Transcriptional Control of Iron Levels

Iron metabolism is precisely regulated by the concerted action of various genes and proteins, with hepcidinplaying a central role as a circulating peptide hormone primarily produced in the liver.^[3] Hepcidin exerts its control over systemic iron absorption and recycling by interacting with ferroportin, the major cellular iron export protein, thereby modulating iron flux.^[3] Genetic factors also contribute significantly to this regulation, as evidenced by variants in genes like TFR2 which are implicated in the physiological control of serum iron levels.^[3] Furthermore, the hereditary hemochromatosis protein HFEinfluences ferritin levels by inhibiting cellular iron export, highlighting a key regulatory mechanism and feedback loop within iron metabolism.^[13]

Proteolytic and Post-Translational Regulation

Beyond transcriptional control, iron homeostasis is also subject to sophisticated post-translational regulatory mechanisms, including proteolytic processing. Matriptase-2, encoded by the TMPRSS6 gene, functions as a proteolytic regulator of iron balance.^[14] This enzyme precisely cleaves and inactivates key proteins involved in iron metabolism, thereby fine-tuning the systemic response to iron availability and illustrating a critical form of protein modification. Additionally, the PCSK7gene locus has been associated with soluble transferrin receptor levels, suggesting broader network interactions and pathway crosstalk that contribute to the overall regulation of iron status, which in turn impacts ferritin levels.^[1]

Pathophysiological Implications of Iron Imbalance

Dysregulation within these intricate iron metabolic pathways can lead to significant health consequences, including iron-overload diseases like hereditary hemochromatosis or iron deficiency anemia.^[3]Elevated serum ferritin is a primary indicator for screening hereditary hemochromatosis, demonstrating the clinical relevance of these pathways.^[15] Specific genetic mutations, such as those found in TMPRSS6, directly cause iron-refractory iron deficiency anemia (IRIDA), illustrating how pathway dysregulation manifests as distinct disease phenotypes.^[16]An imbalanced iron status is also broadly associated with other systemic disorders, including diabetes mellitus, inflammation, and various neurological and cardiovascular diseases, underscoring the vital, integrative role of iron homeostasis in overall physiological health.^[3]

Diagnostic and Monitoring Utility

Ferritin serves as a crucial indicator of the body’s iron storage and the erythropoietic demand for iron.^[1] Its is fundamental for the quantitative assessment of overall body iron status, providing valuable insights into an individual’s iron metabolism.^[12]This makes ferritin a vital diagnostic tool for identifying both iron deficiency and iron overload conditions, as well as for monitoring patient response to therapeutic interventions aimed at modulating iron levels.^[1]The establishment of population norms for serum ferritin further enhances its clinical utility, offering a reliable benchmark for interpreting results and guiding clinical decision-making.^[11]

Genetic Influences and Risk Stratification

The physiological regulation of ferritin levels is influenced by genetic factors, which contribute to the observed variability in iron metabolism among individuals.^[3]Research has identified genetic associations, such as a correlation between ferritin levels and variants in theSLC17A1 gene, notably rs17342717 , which is in linkage disequilibrium with the HFE gene variant rs1800562 .^[3] This genetic insight is particularly relevant for conditions like hemochromatosis, where HFE gene variants are known to predispose individuals to iron overload.^[3] Understanding these genetic underpinnings can facilitate personalized medicine approaches, enabling clinicians to identify high-risk individuals for iron-related disorders through genetic screening and implement preventive strategies before significant clinical manifestations occur.^[3]

Ferritin in Iron Overload and Associated Conditions

Serum ferritin is indispensable for the diagnosis and comprehensive screening of iron overload disorders, most notably hereditary hemochromatosis.^[10]Large-scale public health initiatives, such as the Hemochromatosis and Iron Overload Screening (HEIRS) study, have demonstrated the effectiveness of ferritin screening in assessing iron status across diverse adult populations.^[10]Persistently elevated ferritin levels can signify pathological iron accumulation, which, if left unaddressed, can lead to severe complications affecting multiple organ systems.^[5]Therefore, routine ferritin assessment aids in early detection, allowing for timely therapeutic interventions that can prevent disease progression, mitigate long-term organ damage, and improve patient outcomes.^[5]

Frequently Asked Questions About Ferritin

These questions address the most important and specific aspects of ferritin based on current genetic research.

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1. I’m always tired. Could my iron be off, even if I eat well?

Yes, persistent fatigue and weakness are classic symptoms of iron deficiency, which is often reflected by low ferritin levels. While diet is crucial, your body’s ability to absorb and use iron can also be influenced by your genes. Genetic variations, even in genes likeTMPRSS6, can impact how efficiently your body regulates iron, potentially leading to low iron stores despite a good diet.

2. My dad had high iron levels. Does that mean I’ll have them too?

It’s possible. High iron levels, often seen as elevated ferritin, can be inherited. For instance, specific variations in theHFE gene, such as C282Y, are strongly linked to hereditary hemochromatosis, a condition where your body absorbs and stores too much iron. If your dad has this condition, you might have inherited the genetic predisposition.

3. I feel fine, but my doctor said my iron levels were high. Is that actually a big deal?

Yes, even if you feel fine, consistently high iron levels (elevated ferritin) can be a significant concern. Over time, excessive iron accumulation can damage vital organs like your liver, heart, and pancreas, leading to serious health issues. This is especially true if you have genetic predispositions, such as variants in theHFE gene, which cause your body to store too much iron.

4. I just got over a bad cold, and my iron test was high. Does being sick change my results?

Yes, absolutely. Ferritin levels can temporarily rise when your body is fighting an infection or inflammation, even if your actual iron stores haven’t increased. Ferritin acts as an “acute-phase reactant,” meaning its levels can be elevated during sickness or inflammation. This can make it tricky to interpret your true iron status right after an illness.

5. Does it really matter what time of day I get my blood drawn for an iron test?

Yes, the timing of your blood draw can influence your ferritin results. Studies have shown that ferritin levels can vary throughout the day, a phenomenon known as diurnal variation. To get the most accurate picture of your iron stores, it’s often best to have your blood sample collected at a consistent time, usually in the morning, to minimize these daily fluctuations.

6. My sister and I eat similarly, but her iron is always low and mine is normal. Why the difference?

Even with similar diets, individual differences in iron levels can be significantly influenced by genetics. Variations in genes like TMPRSS6 or TFR2play a role in how your body regulates iron absorption and metabolism. These genetic factors can mean that you and your sister process iron differently, leading to varying ferritin levels despite similar lifestyles.

7. I heard that women often have more iron issues. Is that true?

Yes, iron deficiency is indeed a global public health concern that disproportionately affects women, particularly those of childbearing age, primarily due to menstrual blood loss. Additionally, physiological factors like menopausal status can influence ferritin levels, making iron metabolism distinct between genders. Genetic factors, while present in both, can interact with these physiological differences.

8. Can simply taking iron supplements fix my low iron, or is there more to consider?

While iron supplements are often effective for low iron, it’s not always a simple fix. Your body’s ability to absorb and utilize iron can be influenced by your genetic makeup. For example, some genetic variations might affect how efficiently your body regulates iron, meaning that even with supplements, you might need a tailored approach or further investigation into the underlying cause of your low levels.

9. I’m planning to get pregnant. Should I be extra concerned about my iron levels?

Yes, it’s particularly important to monitor your iron levels, indicated by ferritin, when planning pregnancy. Iron deficiency is common among women and can significantly impact both maternal and fetal health. Understanding your baseline iron status and any genetic predispositions, which might influence your iron needs, allows for appropriate nutritional interventions to support a healthy pregnancy.

10. If my iron levels are high, will my doctor suggest a genetic test?

If you have unexplained high iron levels (elevated ferritin), especially if there’s a family history of iron overload, your doctor might recommend genetic testing. This is because conditions like hereditary hemochromatosis, caused by variants in genes likeHFE, are a common cause of excessive iron accumulation. Identifying these genetic factors can guide proper management and help prevent potential organ damage.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Oexle K, et al. “Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels.”Hum Mol Genet, 2011.

[2] McLaren CE, et al. “Genome-wide association study identifies genetic loci associated with iron deficiency.” PLoS One, 2011.

[3] Pichler I et al. “Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.” Hum Mol Genet, vol. 20, no. 5, 2011, pp. 1027–1032.

[4] Benyamin, B., et al. “Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.”Am J Hum Genet, vol. 83, no. 6, 2008, pp. 693-702. PMID: 19084217.

[5] Lieu, P. T., et al. “The roles of iron in health and disease.”Mol Aspects Med, vol. 22, 2001, pp. 1–87.

[6] Milman N, Pedersen NS, Visfeldt J. “Serum ferritin in healthy Danes: relation to marrow haemosiderin iron stores.”Dan Med Bull, vol. 30, 1983, pp. 115–120.

[7] Ballas, S. K. “Normal serum iron and elevated total iron-binding capacity in iron-deficiency states.”Am J Clin Pathol, vol. 71, 1979, pp. 401–403.

[8] Whitfield, J. B., et al. “Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins.” Am J Hum Genet, vol. 66, 2000, pp. 1246–1258.

[9] Lee, P. L., et al. “The effect of transferrin polymorphisms on iron metabolism.”Blood Cells Mol Dis, vol. 25, 1999, pp. 374–379.

[10] Adams, P. C., et al. “Hemochromatosis and iron-overload screening in a racially diverse population.” N Engl J Med, vol. 352, 2005, pp. 1769–1778.

[11] Custer EM, Finch CA, Sobel RE, Zettner A. “Population norms for serum ferritin.”J Lab Clin Med, vol. 126, 1995, pp. 88–94.

[12] Cook JD, Flowers CH, Skikne BS. “The quantitative assessment of body iron.” Blood, vol. 101, 2003, pp. 3359–3364.

[13] Davies P.S. and Enns C.A. “Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells.”J. Biol. Chem., vol. 279, 2004, pp. 25085–25092.

[14] Ramsay A.J. et al. “Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis.” Haematologica, vol. 94, 2009, pp. 840–849.

[15] Waalen J, Felitti V.J, Gelbart T, Beutler E. “Screening for hemochromatosis by measuring ferritin levels: a more effective approach.”Blood, vol. 111, 2008, pp. 3373–3376.

[16] Finberg K.E. et al. “Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).”Nat. Genet., vol. 40, 2008, pp. 569–571.