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Nutrigenomics for Sport and Exercise Performance
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Nanci S. Guest, Marc Sicova, Ahmed El-Sohemy
Three SNPs, TMPRSS6 (rs4820268), TF (rs3811647), and TFR2 (rs7385804), have been associated with low iron status and may modify an individual's risk for low iron status (101). The three SNPs are known to regulate the expression of the protein hepcidin (67, 124, 136). Hepcidin inhibits iron transport in the plasma by binding to ferroprotein, a transmembrane protein that transports iron from the inside to the outside of the cell (136). In addition, the oxygen carrying capacity of the two iron containing proteins, haemoglobin and myoglobin, is reduced due to low iron anaemia, impairing performance (27, 60). Low iron status can be predicted by certain combinations of genotypes within SNPs of the TMPRSS6, TF, and TRF2 genes. Those with the GG genotype of TMPRSS6 (rs4820268) possess an elevated risk for low transferrin saturation and haemoglobin, compared to A-allele carriers who possess a typical risk (46, 101). Those with the AA genotype of TF (rs3811647) are more likely to possess low ferritin but high transferrin saturations compared to G-allele carriers (101). Those with the CC genotype of TFR2 (rs7385804) are more likely to experience decreased haematocrit, mean corpuscular volume, and RBC count compared to A-allele carriers. Genotyping of these three SNPs can be carried out and inputted into an algorithm to help predict individual risk for low iron status (17, 118). If an athlete is at risk for low iron, modifications can be made through diet or supplementation to offset their risk. Despite being at an increased risk for low iron status, athletes should monitor their supplemental iron intake and serum ferritin to ensure they are not consuming excessive amounts of iron. Indeed, variation in the HFE gene has been shown to influences one's susceptibility to iron overload (hemochromatosis) (16, 116).
A deep dive into future therapies for microcytic anemias and clinical considerations
Published in Expert Review of Hematology, 2023
François Rodrigues, Tereza Coman, Guillemette Fouquet, Francine Côté, Geneviève Courtois, Thiago Trovati Maciel, Olivier Hermine
Iron-refractory iron deficiency anemia (IRIDA) is a rare recessive microcytic anemia resulting from mutations of TMPRSS6 [84]. TMPRSS6 encodes for a type II membrane bound serine protease called matriptase II. Loss of matriptase II results in hypochromic microcytic anemia, normal serum ferritin levels, low transferrin saturation, and normal or elevated hepcidin levels [85,86]. Patients with IRIDA present with iron deficiency that is unresponsive to oral supplementation, since hyperhepcidinemia prevents intestinal iron absorption [84]. Mechanistically, matriptase II inhibits hepcidin activation by cleaving hemojuvelin, a key protein of the BMP-SMAD signal enhancing complex located on the hepatocyte membrane [87]. IRIDA is only incompletely corrected by parenteral iron administration, suggesting that an innovative therapy targeting the hepcidin pathway could be more effective.
A perspective on RNA interference-based therapeutics for metabolic liver diseases
Published in Expert Opinion on Investigational Drugs, 2021
Hereditary hemochromatosis (HHC) is a common genetic disorder affecting approximately 1 in 250 individuals from northern European origin [49]. The liver hormone hepcidin plays a central role in the regulation of iron homeostasis by binding to and inhibiting the iron-exporter protein ferroportin which is expressed on enterocytes, hepatocytes, and macrophages [50]. HHC is caused by inappropriately low expression of hepcidin leading to iron overload and accumulation in different organs including the liver. TMPRSS6 is a negative regulator of hepatocyte hepcidin expression and therefore is being considered as a potential treatment target for HHC. SLN124 is a GalNAc-siRNA conjugate that was developed to specifically target hepatocyte TMPRSS6 expression [51]. Subcutaneous injection of SLN124 significantly reduced TMPRSS6 gene expression in wild type mice and increased hepatic hepcidin mRNA expression and hepcidin protein levels in the plasma. Similar findings were noted in an animal model of HHC (HFE knockout mice) with SLN124 resulting in a significant decrease in TMPRSS6 levels, serum iron and transferrin saturation, reductions that lasted nearly 6 weeks following a single dose of SLN124 .
An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment
Published in Hemoglobin, 2023
Mohammadreza Saeidnia, Pooria Fazeli, Arghavan Farzi, Maryam Atefy Nezhad, Mojtaba Shabani-Borujeni, Mehran Erfani, Gholamhossein Tamaddon, Mehran Karimi
Transmembrane protein serine 6 (TMPRSS6) sharply decreases intrinsic hepcidin production. In turn, preclinical study on β-TI mouse model demonstrated that the TMPRSS6 gene deletion, interrupting the gene by using antisense oligonucleotides and small RNAs could remedy iron overload and consequently amend erythropoiesis [97]. A Phase 2, multicenter, open-label study by Ionis Pharmaceuticals Inc. (Carlsbad, CA, USA) [111] was conducted to investigate the influences of IONIS TMPRSS6-LRx in adult NTDT patients (≥18 years of age). A single IONIS TMPRSS6-LRx administration at multiple dose levels was injected into participants subcutaneously every 4 weeks for 24 months. The results showed the Hb levels rose and liver iron levels dropped [94].