Genetic Factors in Iron Homeostasis and Deficiency Anemia

Iron balance in the human body is maintained through a finely tuned network of absorption, transport and storage processes, orchestrated by key regulatory genes. The peptide hormone hepcidin, synthesised in the liver, serves as the principal negative regulator by binding to the iron exporter ferroportin and triggering its degradation. Variants in the HFE gene (notably C282Y and H63D) modulate hepcidin expression and predispose carriers to either iron overload or deficiency. TMPRSS6, encoding the protease matriptase-2, downregulates hepcidin transcription; common polymorphisms in this gene can lead to iron-refractory iron deficiency anaemia or, conversely, enhanced absorption in certain populations. Transferrin and its receptor govern iron delivery to erythroid precursors, while ferroportin variants affect cellular iron egress. Genome-wide association studies have identified additional loci influencing serum ferritin and transferrin saturation, illuminating the polygenic nature of iron traits. Ethnic differences in allele frequencies contribute to the global distribution of iron deficiency anaemia, particularly among women of reproductive age and young children. Insights into these genetic determinants underpin risk stratification, guide dietary recommendations and inform the development of molecular therapies aimed at restoring iron homeostasis.

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Technical terms

Iron homeostasis: regulation of iron absorption, transport and storage to maintain physiological balance.

Hepcidin: liver-derived peptide hormone that controls systemic iron levels by inducing ferroportin degradation.

Ferroportin: transmembrane protein responsible for exporting iron from enterocytes and macrophages into the circulation.

Single nucleotide polymorphism (SNP): common genetic variant at a single DNA base pair that may affect gene function or regulation.

Genome-wide association study (GWAS): systematic analysis linking genetic variants across the genome to specific traits, such as serum iron measures.

References

1. Differences in the frequency of genetic variants associated with iron imbalance among global populations. PLOS ONE (2020).
2. The Association of TMPRSS6 Gene Polymorphism and Iron Intake with Iron Status among Under-Two-Year-Old Children in Lombok, Indonesia. Nutrients (2019).
3. Associations of Common Variants in HFE and TMPRSS6 Genes with Hepcidin‐25 and Iron Status Parameters in Patients with End‐Stage Renal Disease. Disease Markers (2019).