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A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?
Open AccessArticle

The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients

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General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
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Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy
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Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy
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Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy
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Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy
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Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
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Department of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
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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
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Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Katsutoshi Tokushige
Cancers 2021, 13(8), 1783; https://doi.org/10.3390/cancers13081783
Received: 11 March 2021 / Revised: 31 March 2021 / Accepted: 1 April 2021 / Published: 8 April 2021
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)
Dyslipidemia is a hallmark of nonalcoholic fatty liver disease (NAFLD) and the rs599839 variant in the CELSR2-PSRC1-SORT1 genetic cluster, has been associated with a protection against cardiovascular events. Here, we revealed a novel link between the rs599839 variant and hepatocellular carcinoma (HCC) whose onset in the context of NAFLD is rapidly increasing. We found that the rs599839 variant disentangled the risk of HCC from that of cardiovascular abnormalities by modulating SORT1 and PSRC1 expressions. The latter emerged as a potential modifier of liver carcinogenesis.
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. View Full-Text
Keywords: lipid metabolism; NAFLD; genetic variants; PSRC1; HCC lipid metabolism; NAFLD; genetic variants; PSRC1; HCC
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Figure 1

MDPI and ACS Style

Meroni, M.; Longo, M.; Paolini, E.; Alisi, A.; Miele, L.; De Caro, E.R.; Pisano, G.; Maggioni, M.; Soardo, G.; Valenti, L.V.; Fracanzani, A.L.; Dongiovanni, P. The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients. Cancers 2021, 13, 1783. https://doi.org/10.3390/cancers13081783

AMA Style

Meroni M, Longo M, Paolini E, Alisi A, Miele L, De Caro ER, Pisano G, Maggioni M, Soardo G, Valenti LV, Fracanzani AL, Dongiovanni P. The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients. Cancers. 2021; 13(8):1783. https://doi.org/10.3390/cancers13081783

Chicago/Turabian Style

Meroni, Marica; Longo, Miriam; Paolini, Erika; Alisi, Anna; Miele, Luca; De Caro, Emilia R.; Pisano, Giuseppina; Maggioni, Marco; Soardo, Giorgio; Valenti, Luca V.; Fracanzani, Anna L.; Dongiovanni, Paola. 2021. "The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients" Cancers 13, no. 8: 1783. https://doi.org/10.3390/cancers13081783

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