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Open Access Highly Accessed Research article

The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

Serena Pelusi1, Domenico Girelli2, Raffaela Rametta1, Natascia Campostrini2, Carlo Alfieri3, Michela Traglia45, Paola Dongiovanni1, Giovanna Como3, Daniela Toniolo45, Clara Camaschella4, Piergiorgio Messa3, Silvia Fargion1 and Luca Valenti1*

Author Affiliations

1 Department of Pathophysiology and Transplantation, Internal Medicine, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano, Milano, Italy

2 Department of Medicine, Internal Medicine, Università di Verona, Verona, Italy

3 Nephrology, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milano, Italy

4 San Raffaele Research Institute, Università Vita-Salute, Milano, Italy

5 Institute of Molecular Genetics, CNR Pavia, Italy

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BMC Nephrology 2013, 14:48  doi:10.1186/1471-2369-14-48

Published: 22 February 2013

Abstract

Background

Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD).

Methods

To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry.

Results

Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the “high hepcidin” 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02).

Conclusions

The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.

Keywords:
Anemia; Chronic kidney disease; Erythropoietin; Genetics; Inflammation; Iron; Hemodialysis; Hepcidin; Hfe gene; Matriptase-2; Tmprss6