Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifiesPCSK7as a host risk factor of liver cirrhosis

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Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity forHFEC282Y 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,TFR2and 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 GermanHFEC282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112HFEC282Y homozygotes from Sweden. Only variant rs236918 in thePCSK7gene (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/SwissHFEC282Y homozygotes (P= 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients.Post hoccombined 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.PCSK7variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for theHFEC282Y mutation.

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