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

BACKGROUND AND AIM: p.Cys282Tyr homozygosity is the prevalent genotype in HFE-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). SNP genotyping was performed by RFLP or Taqman 5'-nuclease assays.RESULTS: The rs236918 allele C frequency increased from stage 0-2 to stage 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 to 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, odd ratio (OR) 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 (OR=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. This article is protected by copyright. All rights reserved.