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The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients.
Meroni, Marica; Longo, Miriam; Paolini, Erika; Alisi, Anna; Miele, Luca; De Caro, Emilia Rita; Pisano, Giuseppina; Maggioni, Marco; Soardo, Giorgio; Valenti, Luca Vittorio; Fracanzani, Anna Ludovica; Dongiovanni, Paola.
Afiliação
  • Meroni M; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • Longo M; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy.
  • Paolini E; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • Alisi A; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy.
  • Miele L; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • De Caro ER; Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy.
  • Pisano G; Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy.
  • Maggioni M; Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
  • Soardo G; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • Valenti LV; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • Fracanzani AL; Department of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
  • Dongiovanni P; Clinic of Internal Medicine-Liver Unit Department of Medical Area (DAME), University School of Medicine, Udine, Italy and Italian Liver Foundation AREA Science Park-Basovizza Campus, 34149 Trieste, Italy.
Cancers (Basel) ; 13(8)2021 Apr 08.
Article em En | MEDLINE | ID: mdl-33917919
ABSTRACT
BACKGROUND AND

AIMS:

Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet.

METHODS:

We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125).

RESULTS:

The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR) 5.62; 95% c.i. 1.77-17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05).

CONCLUSIONS:

In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Etiology_studies / Risk_factors_studies Idioma: En Revista: Cancers (Basel) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Etiology_studies / Risk_factors_studies Idioma: En Revista: Cancers (Basel) Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Itália