Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis

Sara Pelucchi, Stefania Galimberti, Federico Greni, Raffaela Rametta, Raffaella Mariani, Irene Pelloni, Domenico Girelli, Fabiana Busti, Giulia Ravasi, Maria Grazia Valsecchi, Luca Valenti, Alberto Piperno

Research output: Contribution to journalArticle

Abstract

Background and Aim: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. Methods: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0–2), moderate (stage: 3–4), and severe fibrosis/cirrhosis (stage: 5–6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5′-nuclease assays. Results: The rs236918 allele C frequency increased from stages 0–2 to 5–6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. Conclusions: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.

Original languageEnglish
Pages (from-to)1342-1348
Number of pages7
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume31
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

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Proprotein Convertases
Hemochromatosis
Liver Cirrhosis
Fibrosis
Genotype
Gene Frequency
Odds Ratio
Penetrance
Liver
Homozygote
Genetic Markers
Restriction Fragment Length Polymorphisms
Single Nucleotide Polymorphism
Hepatocellular Carcinoma
Iron
Alleles

Keywords

  • iron
  • Ishak score
  • p.Cys282Tyr
  • PCSK7
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis. / Pelucchi, Sara; Galimberti, Stefania; Greni, Federico; Rametta, Raffaela; Mariani, Raffaella; Pelloni, Irene; Girelli, Domenico; Busti, Fabiana; Ravasi, Giulia; Valsecchi, Maria Grazia; Valenti, Luca; Piperno, Alberto.

In: Journal of Gastroenterology and Hepatology (Australia), Vol. 31, No. 7, 01.07.2016, p. 1342-1348.

Research output: Contribution to journalArticle

Pelucchi, S, Galimberti, S, Greni, F, Rametta, R, Mariani, R, Pelloni, I, Girelli, D, Busti, F, Ravasi, G, Valsecchi, MG, Valenti, L & Piperno, A 2016, 'Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis', Journal of Gastroenterology and Hepatology (Australia), vol. 31, no. 7, pp. 1342-1348. https://doi.org/10.1111/jgh.13315
Pelucchi, Sara ; Galimberti, Stefania ; Greni, Federico ; Rametta, Raffaela ; Mariani, Raffaella ; Pelloni, Irene ; Girelli, Domenico ; Busti, Fabiana ; Ravasi, Giulia ; Valsecchi, Maria Grazia ; Valenti, Luca ; Piperno, Alberto. / Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis. In: Journal of Gastroenterology and Hepatology (Australia). 2016 ; Vol. 31, No. 7. pp. 1342-1348.
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abstract = "Background and Aim: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. Methods: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0–2), moderate (stage: 3–4), and severe fibrosis/cirrhosis (stage: 5–6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5′-nuclease assays. Results: The rs236918 allele C frequency increased from stages 0–2 to 5–6 (7.1{\%} vs 13.6{\%}, vs 21.9{\%}, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2{\%}) compared with only 17{\%} in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28{\%}. Conclusions: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.",
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T1 - Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis

AU - Pelucchi, Sara

AU - Galimberti, Stefania

AU - Greni, Federico

AU - Rametta, Raffaela

AU - Mariani, Raffaella

AU - Pelloni, Irene

AU - Girelli, Domenico

AU - Busti, Fabiana

AU - Ravasi, Giulia

AU - Valsecchi, Maria Grazia

AU - Valenti, Luca

AU - Piperno, Alberto

PY - 2016/7/1

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N2 - Background and Aim: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. Methods: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0–2), moderate (stage: 3–4), and severe fibrosis/cirrhosis (stage: 5–6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5′-nuclease assays. Results: The rs236918 allele C frequency increased from stages 0–2 to 5–6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. Conclusions: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.

AB - Background and Aim: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. Methods: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0–2), moderate (stage: 3–4), and severe fibrosis/cirrhosis (stage: 5–6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5′-nuclease assays. Results: The rs236918 allele C frequency increased from stages 0–2 to 5–6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. Conclusions: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.

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