Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis

Luca Valenti, Anna Ludovica Fracanzani, Raffaela Rametta, Mirella Fraquelli, Giulia Soverini, Serena Pelusi, Paola Dongiovanni, Dario Conte, Silvia Fargion

Research output: Contribution to journalArticlepeer-review


Background & Aims: 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.

Original languageEnglish
Pages (from-to)1319-1325
Number of pages7
JournalJournal of Hepatology
Issue number6
Publication statusPublished - Dec 2012


  • Cirrhosis
  • Genetics
  • Hepatocellular carcinoma
  • Hepcidin
  • Hereditary hemochromatosis
  • HFE
  • Iron
  • Penetrance

ASJC Scopus subject areas

  • Hepatology


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