Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis

Abstract

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

PNPLA3 gene in liver diseases

“…One study from Italy reported a significant association between PNPLA3 and steatosis/advanced fibrosis in 174 patients with hereditary hemochromatosis and homozygous for the HFE C282Y mutation [47]. However, the association with cirrhosis was not replicated in another study that also included patients of European descent [48]. In patients with Wilson disease, carriers of the mutant rs738409[G] allele had a higher prevalence of steatosis [49].…”

Serum Hepcidin Level and Human Factors Engineering (HFE) C282Y Mutation in Egyptian Children with Beta-Thalassemia

“…But individuals with Cys282Tyr homozygosity might present with abnormal iron tests with or without clinical symptoms and with or without proving evidence of iron overload [27].…”

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

“…A metaanalysis of GWAS results on the soluble transferrin receptor (sTfR) and ferritin reported a novel association between sTfR and the variation in the proprotein convertase 7 (PCSK7) gene and the iron overload [13]. These polymorphisms were extensively studied by Stickel et al [14], who showed that the PCSK7 variant rs236918 was a risk factor for the development of cirrhosis in hereditary hemochromatosis (HH).…”