Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with <i>HFE</i>‐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

doi:10.1111/jgh.13315

Cited by 18 publications

(20 citation statements)

References 42 publications

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“…Previous studies revealed an association of low-frequency PCSK7 missense variants with circulating lipids (11)(12)(13), suggesting that altered PCSK7 function accounts for this phenotype, and the noncoding variant, rs236918, has also been associated with liver damage in patients with hereditary hemochromatosis (20,21). Here, we found that the rs236918 C minor allele was associated with increased circulating triglycerides in NAFLD patients and with dyslipidemia in the UKBBC (12,13).…”

Section: Discussionsupporting

confidence: 63%

“…PCSK7, also known as PC7 (15,16), is a widely expressed transmembrane protease (17). The noncoding rs236918 PCSK7 variant (NC_000011.10:g.117220893 G>C) has been associated with shedding of membrane transferrin receptor (18,19) and with liver damage during iron overload (20,21), but the mechanism underlying the clinical phenotype remains unclear. Moreover, the impact of PCSK7 variation on hepatic fat accumulation and liver damage in patients with NAFLD has not been evaluated so far, and the underlying mechanism remained elusive.…”

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confidence: 99%

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PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients

Dongiovanni

Meroni

Baselli

et al. 2019

Journal of Lipid Research

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Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P < 0.05). The rs236918 C allele was associated with upregulation of a new “intra-PCSK7” long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.

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Section: Discussionsupporting

confidence: 63%

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confidence: 99%

PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients

Dongiovanni

Meroni

Baselli

et al. 2019

Journal of Lipid Research

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“…Our future work will explore the role of PCSK7 in collagen VI proteolysis and work is underway to identify any PRO-C6 fragments in our model. It is noteworthy that PCSK7 missense variants identified in GWAS studies are associated with liver fibrosis (69). More recently a PCSK7 variant has been shown to lead to increased intracellular PCSK7 expression and secretion from hepatocytes, potentially linking dyslipidemia with a tendency to more severe liver damage in high risk individuals (70).…”

Section: Discussionmentioning

confidence: 99%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

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“…29 In contrast, cirrhosis was significantly associated with the patatin-like phospholipase domain-contaιnmg-3 (PNPLA3) I148M polymorphism (rs738409) in Italian patients with hemochromatosis and p.C282Y homozygosity whose body mass index was < 25 kg/m 2 . 30 PCSK7 (proprotein convertase subtilisin/kexin type 7) rs236918 C allele was a risk factor for cirrhosis in 244 German and Austrian/Swiss 31 and 187 Italian 32 patients with hemochromatosis and p.C282Y homozygosity, but not 112 Swedish patients with hemochromatosis and p.C282Y homozygosity. 31…”

Section: Discussionmentioning

confidence: 99%

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes

Barton

McLaren

Chen

et al. 2018

Annals of Hepatology

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

Abstract: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.

Cited by 18 publications

References 42 publications

PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients

PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes

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