Genetics of Iron Metabolism
Iron metabolism involves absorption, transport, storage, and utilisation of iron for haemoglobin synthesis and cellular processes. Genetic variants in iron metabolism genes affect iron homeostasis, with implications for both iron deficiency and iron overload conditions.
This page is for educational and informational purposes only. Not a diagnostic tool. Always consult a qualified healthcare provider.
What is Iron Metabolism?
Iron is essential for oxygen transport (haemoglobin), cellular respiration (iron-sulphur clusters in electron transport chain), and DNA synthesis. Iron homeostasis is tightly regulated by hepcidin (HAMP), which controls ferroportin-mediated iron efflux. HFE variants (C282Y, H63D) cause hereditary haemochromatosis through impaired hepcidin upregulation, leading to iron overload. TMPRSS6 variants cause iron-refractory iron deficiency anaemia. In chronic illness, the acute phase response elevates hepcidin, causing anaemia of chronic disease by sequestering iron. Ferritin is both an iron storage protein and an acute phase reactant — elevated ferritin in Long COVID reflects inflammation, not iron excess.
Biological pathways commonly discussed in relation to Iron Metabolism
Research into Iron Metabolism, Transport, and Haemostasis has highlighted several biological pathways that may be relevant. Genetic variants within these pathways may influence individual susceptibility, symptom severity, or the trajectory of the condition.
Iron Absorption
Dietary ferric iron (Fe3+) is reduced by CYBRD1 (DCYTB) at the duodenal brush border and taken up by DMT1 (SLC11A2). Basolateral efflux via ferroportin (SLC40A1) exports iron to plasma transferrin. HFE regulates transferrin receptor 1 (TFRC) competition at enterocyte membranes.
Hepcidin Axis
Hepcidin (HAMP) is the master iron regulator, produced by hepatocytes in response to iron stores (via BMP-SMAD signalling) and inflammation (via IL-6/STAT3). Hepcidin binds ferroportin, triggering its degradation and blocking iron efflux. TMPRSS6 (matriptase-2) suppresses hepcidin by cleaving BMP co-receptors.
Iron Transport
Transferrin (TF) carries iron in plasma to transferrin receptors (TFRC, TFR2). Intracellular iron storage occurs in ferritin (FTH1, FTL). Variants in ferritin genes cause hyperferritinaemia-cataract syndrome or hereditary ferritinopathy.
Mitochondrial Iron
Iron is essential for haem synthesis (HMBS, FECH) and iron-sulphur cluster assembly (NFU1, BOLA3) in mitochondria. Impaired mitochondrial iron handling contributes to sideroblastic anaemia and mitochondrial dysfunction.
Key genes studied in relation to Iron Metabolism
The following genes have been studied in relation to Iron Metabolism, Transport, and Haemostasis. These genes span the biological pathways most commonly discussed in this area of research.
Genetic variants commonly discussed
The following genetic variants (SNPs) are found in genes that have been studied in relation to Iron Metabolism. Each variant represents a position in the genome where individuals may carry different alleles.
How personal DNA data may provide educational insights
Consumer DNA files from 23andMe, AncestryDNA, and MyHeritage contain raw SNP data. When you upload your file to ChronicDNA, the analysis engine checks your genotype against a curated panel of 80+ genes selected for their relevance to Long COVID, ME/CFS, and connected biological pathways - some of which may relate to areas such as Iron Metabolism.
This is not a diagnostic service. Genetic variants do not determine whether you have Iron Metabolism, nor do they predict your clinical outcomes. The report is educational - it explains which variants you carry, what the research says about them, and how they fit into the biological pathways most relevant to chronic illness. All results should be discussed with a qualified healthcare provider.
Related conditions and pathways
Iron Metabolism shares biological pathways and genetic associations with the following related conditions and areas of research.
Frequently asked questions
What is the HFE C282Y variant?
HFE C282Y is the primary variant causing hereditary haemochromatosis, the most common autosomal recessive genetic condition in Northern Europeans (~1 in 200 C282Y homozygotes). It impairs HFE protein interactions with transferrin receptor, reducing hepcidin signalling and causing unregulated intestinal iron absorption. Without treatment, progressive iron overload damages liver, heart, joints, and endocrine organs.
Why is ferritin elevated in Long COVID?
Ferritin is both an iron storage protein and an acute phase reactant — its synthesis is driven by IL-6 and other pro-inflammatory cytokines. Elevated ferritin in Long COVID primarily reflects ongoing inflammation rather than iron excess. Transferrin saturation and serum iron provide better indicators of functional iron availability.
How does hepcidin cause anaemia of chronic disease?
During inflammation, IL-6 (and other cytokines) stimulate hepatic hepcidin (HAMP) production via STAT3. Hepcidin binds ferroportin on macrophages and enterocytes, blocking iron efflux and sequestering iron intracellularly. This reduces circulating iron, limiting haemoglobin synthesis and causing normochromic normocytic anaemia even when total body iron stores are adequate.
Which iron metabolism genes are studied?
Key genes include HFE, HAMP, TMPRSS6, SLC11A2, SLC40A1, TFRC, TFR2, FTH1, FTL, CYBRD1, and BMP6. These cover iron absorption, hepcidin regulation, plasma transport, and cellular iron storage.
Explore DNA insights
If you already have DNA data from 23andMe, AncestryDNA, or MyHeritage, upload your raw file to ChronicDNA and receive a personalised educational report covering genes studied in relation to Iron Metabolism and connected biological pathways.
Get Your Personalised DNA ReportInformational and educational only · Not a diagnostic tool · GDPR compliant
5 genes · 6 variants analysed in relation to Iron Metabolism