title: Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis.
abstract: OBJECTIVE
  Hereditary hemochromatosis (HH) is most frequently related to homozygosity for the p.C282Y HFE mutation (C282Y(+/+)), hampering hepcidin induction in response to iron. The rs855791 polymorphism, encoding for the p.A736V variant of TMPRSS6 regulating hepcidin, influences iron status in the population. The aim of this study was to assess the influence of rs855791 on the penetrance and clinical expression of HH.
  
  
  METHODS
  We retrospectively considered 315 HH patients (163 C282Y(+/+), and 152 with other HFE genotypes) evaluated at the time of diagnosis, and 271 healthy controls with normal iron parameters, residents of Northern Italy; TMPRSS6 genotype was assessed by allele specific polymerase chain reaction.
  
  
  RESULTS
  The p.736V variant determining higher hepcidin release was under-represented in the patients (p=0.0023), independently of the presence of the C282Y(+/+) genotype, and the p.736V/V genotype protected from HH independently of age and sex (OR of HH for p.736A/A: 2.57, 1.3-4.1 and for p.736A/V: 1.84, 1.1-3.2). In the 96 C282Y(+/+) male patients without chronic viral hepatitis and alcohol abuse, the "high hepcidin" p.736V allele was negatively associated with cirrhosis independently of age, ferritin, ALT levels, and alcohol intake (OR 3.93, 95% C.I. 1.17-14.61 for the p.736A variant), and with the cumulative incidence of hepatocellular carcinoma (17% p.736A/A, 4% p.736A/V, 0 p.736V/V, p=0.05).
  
  
  CONCLUSIONS
  The p.A736V TMPRSS6 polymorphism is likely a modifier of HH expression. Additional studies are warranted to validate these findings in other cohorts and test their potential relevance for the clinical management of HH patients.
authors.affiliation: Department of Internal Medicine, UO Medicina Interna 1B, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy. luca.valenti@unimi.it
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Mirella
authors.initials: M
authors.lastname: Fraquelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Soverini
authors.forename: Serena
authors.initials: S
authors.lastname: Pelusi
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Dario
authors.initials: D
authors.lastname: Conte
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human