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.

Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis / L. Valenti, A.L. Fracanzani, R. Rametta, M. Fraquelli, G. Soverini, S. Pelusi, P. Dongiovanni, D. Conte, S. Fargion. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 57:6(2012 Dec), pp. 1319-1325. [10.1016/j.jhep.2012.07.041]

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

L. Valenti;A.L. Fracanzani;R. Rametta;SOVERINI, GIULIA;S. Pelusi;P. Dongiovanni;D. Conte;S. Fargion
2012-12

Abstract

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.
Settore MED/09 - Medicina Interna
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0168827812006174-main.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 841.01 kB
Formato Adobe PDF
841.01 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
1-s2.0-S0168827812006174-main.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 841.01 kB
Formato Adobe PDF
841.01 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/208753
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 28
  • ???jsp.display-item.citation.isi??? 26
social impact