Association of common\xa0TMPRSS6 and TF gene variants with hepcidin and iron status in healthy rural Gambians

Momodou W Jallow,Susana Campino,Carla Cerami,Andrew M Prentice

doi:10.1038/s41598-021-87565-5

Momodou W Jallow, Susana Campino + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-87565-5

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Abstract

Genome-wide association studies in Europeans and Asians have identified numerous variants in the transmembrane protease serine 6 (TMPRSS6) and transferrin (TF) genes that are associated with changes in iron status. We sought to investigate the effects of common TMPRSS6 and TF gene SNPs on iron status indicators in a cohort of healthy Africans from rural Gambia. We measured iron biomarkers and haematology traits on individuals participating in the Keneba Biobank with genotype data on TMPRSS6 (rs2235321, rs855791, rs4820268, rs2235324, rs2413450 and rs5756506) and TF (rs3811647 and rs1799852), n = 1316. After controlling for inflammation, age and sex, we analysed the effects of carrying either single or multiple iron-lowering alleles on iron status. TMPRSS6 rs2235321 significantly affected plasma hepcidin concentrations (AA genotypes having lower hepcidin levels; F ratio 3.7, P = 0.014) with greater impact in individuals with low haemoglobin or ferritin. No other TMPRSS6 variant affected hepcidin. None of the TMPRSS6 variants nor a TMPRSS6 allele risk score affected other iron biomarkers or haematological traits. TF rs3811647 AA carriers had 21% higher transferrin (F ratio 16.0, P < 0.0001), 24% higher unsaturated iron-binding capacity (F ratio 12.8, P < 0.0001) and 25% lower transferrin saturation (F ratio 4.3, P < 0.0001) compared to GG carriers. TF rs3811647 was strongly associated with transferrin, unsaturated iron-binding capacity (UIBC) and transferrin saturation (TSAT) with a single allele effect of 8–12%. There was no association between either TF SNP and any haematological traits or iron biomarkers. We identified meaningful associations between TMPRSS6 rs2235321 and hepcidin and replicated the previous findings on the effects of TF rs3811647 on transferrin and iron binding capacity. However, the effects are subtle and contribute little to population variance. Further genetic and functional studies, including polymorphisms frequent in Africa populations, are needed to identify markers for genetically stratified approaches to prevention or treatment of iron deficiency anaemia.

Highlights

Abbreviations GWAS Genome-wide association studies single nucleotide polymorphism (SNPs) Single nucleotide polymorphisms iron-refractory iron deficiency anaemia (IRIDA) Iron-refractory iron deficiency anaemia transmembrane protease serine 6 (TMPRSS6) Transmembrane protease serine 6 TF Transferrin HFE Haemochromatosis factor allele risk score (ARS) Allele risk score FBC Full blood count RBC Red blood cells transferrin saturation (TSAT) Transferrin saturation sTfR Soluble transferrin receptor unsaturated iron-binding capacity (UIBC) Unsaturated iron binding capacity TIBC Total iron binding capacity
Based upon prior GWAS studies, pathway analysis, availability on the Illumina Exome Array, and having a high minor allele frequency in our Gambian population we studied the effect of six candidate SNPs in TMPRSS6 and two in TF on multiple indices of iron and haematological status in 1316 individuals from 1 to 87 years age, from the Keneba Biobank at the MRCG @ LSHTM, in the Gambia
We found weak evidence that one TMPRSS6 SNP had lower hepcidin levels in the variant (AA) homozygotes with an indication of an allele dose effect

Summary

Introduction

Abbreviations GWAS Genome-wide association studies SNPs Single nucleotide polymorphisms IRIDA Iron-refractory iron deficiency anaemia TMPRSS6 Transmembrane protease serine 6 TF Transferrin HFE Haemochromatosis factor ARS Allele risk score FBC Full blood count RBC Red blood cells TSAT Transferrin saturation sTfR Soluble transferrin receptor UIBC Unsaturated iron binding capacity TIBC Total iron binding capacity. Several genome-wide studies (GWASs) have revealed single nucleotide polymorphism (SNPs) in genes involved in hepcidin regulatory pathways, that are associated with impaired iron status[3,4,5]. The most common SNPs associated with low iron status are in the TMPRSS6 gene, encoding the matriptase-2 protein[6,7,8]. More than 50 SNPs within the TMPRSS6 gene have been reported to be associated with impaired iron status. The most common TF SNP to be associated with the risk of iron deficiency is rs381164717,20–22. This SNP is associated with low iron status in different populations globally, including in African p opulations[23]. Little information exists on the effect TF SNPs on low iron status, in settings with high anaemia burden

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