Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD.

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Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in NAFLD patients. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in NAFLD patients.From a cohort of 328 subjects with histological NAFLD, 23 patients with ferritin >750 ng/ml and positive iron staining, and 25 controls with normal ferritin and negative iron staining were selected. Patients with increased transferrin saturation, anemia, inflammation, and beta-thalassemia trait, HFE genotype at risk of iron overload and Ferroportin mutations were excluded. A panel of 32 iron genes was re-sequenced. Literature and in silico predictions were employed for prioritization of pathogenic mutations.Hyperferritinemia patients had a higher prevalence of potential pathogenic rare variants (73.9% vs 20%, p=0.0002) associated with higher iron stores and more severe liver fibrosis (p<0.05). Ceruloplasmin was the most mutated gene and its variants were independently associated with hyperferritinemia, hepatic siderosis, and more severe liver fibrosis (p<0.05). In the overall cohort, ceruloplasmin variants were independently associated with hyperferritinemia (adjusted OR 5.99, 1.83-19.60; p=0.0009).Variants in non-HFE iron genes, particularly Ceruloplasmin, are associated with hyperferritinemia and increased hepatic iron stores in patients with NAFLD. Carriers of such variants have a more severe liver fibrosis, suggesting that genetic predisposition to hepatic iron deposition may translate into liver disease.Nonalcoholic fatty liver disease (NAFLD) is a common disease with potential evolution to cirrhosis and liver cancer. Increased levels of serum ferritin are often detected in NAFLD patients and have been associated with altered iron metabolism and worse patient outcomes. We found that variants of genes related to iron metabolism, particularly Ceruloplasmin, are associated with high ferritin levels, hepatic iron deposition and more severe liver disease in Italian NAFLD patients.

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Authors: Elena Corradini, Elena Buzzetti, Paola Dongiovanni, Stefania Scarlini, Angela Caleffi, Serena Pelusi, Isabella Bernardis, Paolo Ventura, Raffaela Rametta, Elena Tenedini, Enrico Tagliafico, Anna Ludovica Fracanzani, Silvia Fargion, Antonello Pietrangelo, Luca Vittorio Valenti