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Published on: April 4, 2018
The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients
Marica Meroni1,2, Miriam Longo1,3, Erika Paolini1,4
1General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
Insights
The rs599839 variant protects against dyslipidemia and cardiovascular disease in nonalcoholic fatty liver disease (NAFLD) patients. However, this genetic variant may increase the risk of hepatocellular carcinoma (HCC) by affecting lipid metabolism and cell proliferation.
Area of Science:
- Genetics and Genomics
- Hepatology
- Cardiovascular Medicine
Background:
- Nonalcoholic fatty liver disease (NAFLD) is linked to dyslipidemia and cardiovascular diseases (CVD).
- The rs599839 A>G variant in the CELSR2-PSRC1-SORT1 gene cluster is associated with CVD.
- The impact of rs599839 on NAFLD metabolic traits and liver damage severity is unknown.
Purpose of the Study:
- To investigate the effect of the rs599839 variant on metabolic traits in NAFLD patients.
- To determine the association between rs599839 and the risk and progression of hepatocellular carcinoma (HCC) in NAFLD.
- To explore the relationship between rs599839 and hepatic gene expression.
Main Methods:
- Genotyping of the rs599839 variant in 1426 NAFLD patients, 500,000 UK Biobank participants, and 366 TCGA HCC samples.
- RNA sequencing to evaluate hepatic PSRC1, SORT1, and CELSR2 expressions.
- Statistical analysis to assess associations with metabolic traits, CVD risk, HCC risk, prognosis, and gene expression.
Main Results:
- The rs599839 variant correlated with reduced LDL, improved carotid artery health, and lower hypertension risk in NAFLD patients.
- The G allele of rs599839 was linked to a significantly higher risk of HCC, poor prognosis, and advanced tumor stage, independent of fibrosis.
- Hepatic PSRC1, SORT1, and CELSR2 expressions were elevated in NAFLD patients with the rs599839 variant; SORT1 correlated with lipid metabolism, while PSRC1 correlated with cell proliferation.
Conclusions:
- The rs599839 A>G variant offers protection against dyslipidemia and CVD in NAFLD patients.
- This variant may promote HCC development by altering SORT1 and PSRC1 gene expression, influencing lipid metabolism and cell proliferation.
- The rs599839 variant presents a dual role in NAFLD, offering cardiovascular benefits but increasing HCC risk.
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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