Abstract
Background: Oral iron supplementation is commonly used to treat and prevent anaemia. The transmembrane protease serine 6 gene (TMPRSS6), which encodes matriptase 2, is a negative regulator of hepcidin, the key controller of iron homeostasis. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia. We will investigate the in vivo effects of three previously reported TMPRSS6 variants (rs855791, rs4820268 and rs2235321) on oral iron absorption in non-anaemic volunteers in The Gambia. Methods: A recall-by-genotype study design will be employed. Pre-genotyped participants will be recruited from the West African BioResouce (WABR), which currently contains over 3000 genotyped individuals. Male and female volunteers will be selected based on polymorphisms (rs855791, rs4820268 and rs2235321) in the TMPRSS6 gene in the Gambian population. The effects of a single variant allele at one SNP and the additive effect of two or three variant alleles from either two or all three SNPs will be investigated. Study participants will be given a single oral dose of 400mg ferrous sulfate, and blood samples will be collected at baseline, two hours and five hours post supplementation. Differences in iron absorption between genotype groups will be assessed by measuring the increase in serum iron concentration at five hours post iron ingestion. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption. This may help in guiding future iron intervention strategies, particularly in populations with a high frequency of these SNPs and a high frequency of anaemia. Study registration: ClinicalTrials.gov NCT03341338 14/11/17.
Highlights
Despite aggressive implementation of iron supplementation programs, either alone or in combination with food-based supplementation, the prevalence of anaemia remains high in low- and middle-income countries[1,2]
A single nucleotide polymorphism (SNP) in the transmembrane protease serine 6 gene (TMPRSS6) gene can lead to decreased expression or inactivation of matripase-27, which would lead to inappropriately elevated hepcidin levels, inhibited iron absorption and would thereby result in an increased risk of anaemia[5]
Genome-wide association studies (GWAS) has identified several genetic variants associated with iron status[3,11,15,18,19,20]
Summary
Despite aggressive implementation of iron supplementation programs, either alone or in combination with food-based supplementation, the prevalence of anaemia remains high in low- and middle-income countries[1,2]. A single nucleotide polymorphism (SNP) in the TMPRSS6 gene can lead to decreased expression or inactivation of matripase-27, which would lead to inappropriately elevated hepcidin levels, inhibited iron absorption and would thereby result in an increased risk of anaemia[5]. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption.
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