title: The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis.
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.
authors: Department of Pathophysiology and Transplantation, Internal Medicine, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy.
authors: Serena
authors: S
authors: Pelusi
authors: Domenico
authors: D
authors: Girelli
authors: Raffaela
authors: R
authors: Rametta
authors: Natascia
authors: N
authors: Campostrini
authors: Carlo
authors: C
authors: Alfieri
authors: Michela
authors: M
authors: Traglia
authors: Paola
authors: P
authors: Dongiovanni
authors: Giovanna
authors: G
authors: Como
authors: Daniela
authors: D
authors: Toniolo
authors: Clara
authors: C
authors: Camaschella
authors: Piergiorgio
authors: P
authors: Messa
authors: Silvia
authors: S
authors: Fargion
authors: Luca
authors: L
authors: Valenti
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000097:blood*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D006435:Renal Dialysis / Q000706:statistics & numerical data*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology / Q000534:rehabilitation*; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; C578702:HAMP protein, human; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human