Assessing the Effects of Genetic Variations Within the Hepcidin Pathway Genes on Oral Iron Absorption Using a Genes-in-Action Study Design

Anaemia is a recalcitrant problem in global health, affecting particularly children and childbearing women in sub-Saharan Africa. Anaemia causes impaired growth and cognitive development in children, poor pregnancy outcomes including both maternal and perinatal mortality. Also, it is associated with poor economic growth due to its impact on physical activity.

Mass iron supplementation and food fortification are commonly used to combat anaemia in low- and middle-income countries. This due to the fact that the main driver of anaemia is thought to be nutritional iron deficiency. However, these programs have had little impact in sub-Saharan Africa and new strategies are desperately needed.

Low-cost oral iron tablets and micronutrient powders are routinely given to treat and prevent anaemia in both children and pregnant women. However, often these interventions are frequently ineffective, never very effective, and may even cause harm by increasing susceptibility to infections. Both the aetiology of anaemia and the efficacy of iron absorption are complex processes influenced by multiple factors, including nutritional status, infection and host genetics.

Hepcidin, a 25-amino acid liver-produced hormone is the master regulator of body iron status. Hepcidin controls plasma iron influx through its interaction with ferroportin - the only known cellular iron channel. Hepcidin's binding to ferroportin leads to the degradation and internalisation of the latter, thereby blocking iron traffic from macrophages, hepatocytes and duodenal enterocytes, into the plasma. Hepcidin secretion is dampened by hypoxia, erythroid drive and iron deficiency, to enable iron absorption, whereas, iron sufficiency/overload and infection enhances hepcidin transcription.

Hepcidin transcription is regulated by a number of signals and pathways. At the molecular level, the regulation of hepcidin expression is complex, but one of the key regulators is TMPRSS6 (transmembrane protease serine 6). TMPRSS6 (also called matriptase-2) is a type II transmembrane serine protease principally expressed in the liver. TMPRSS6 indirectly regulates hepcidin transcription, by interfering with the bone morphogenetic protein (BMP), hemojuvelin (HJV), and son of mothers against decapentaplegic homolog (SMAD) signalling pathway. TMPRSS6 decreases hepcidin transcription by cleaving hemojuvelin (HJV), thus, reducing BMP-SMAD signalling. Cleavage of membrane-bound HJV, the BMP receptor, by TMPRSS6 leads to BMP reduction, thereby decreasing BMP, resulting in hepcidin repression as BMP-HJV signalling is required for hepcidin transcription. TMPRSS6 is the main negative regulator of hepcidin expression and functional variants leas to iron-refractory iron deficiency anaemia (IRIDA).