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

ABSTRACT: 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.

SUBMITTER: Dongiovanni P

PROVIDER: S-EPMC6547640 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Dongiovanni Paola P Meroni Marica M Baselli Guido G Mancina Rosellina M RM Ruscica Massimiliano M Longo Miriam M Rametta Raffaela R Cespiati Annalisa A Pelusi Serena S Ferri Nicola N Ranzani Valeria V Nobili Valerio V Pihlajamaki Jussi J Fracanzani Anna Ludovica AL Badiali Sara S Petta Salvatore S Fargion Silvia S Romeo Stefano S Kozlitina Julia J Valenti Luca L

Journal of lipid research 20190327 6

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 Dalla ...[more]

PMID: 30918065

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Project description:ObjectivePatients treated with statins for dyslipidemia may still have a residual risk of atherosclerotic cardiovascular disease (ASCVD). To determine whether genetic variants in the cholesteryl ester transport protein (CETP), rs3764261 (C>A), rs708272 (G>A), and rs12149545 (G>A) affect ASCVD risk, we studied the association of these variants with dyslipidemia in statin-treated patients.Patients and methodsWe included 299 adult Thai patients treated with a statin (95 men and 204 women). Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. We used logistic regression models adjusted for potential confounders of age, body mass index, blood pressure, insulin resistance, and statin dosage to analyze the association between CETP variants and atherogenic lipoprotein patterns.ResultsCETP polymorphisms of rs3764261 and rs708272, but not rs12149545, were significantly associated with high-density lipoprotein cholesterol (HDL-C), apoA-I, triglycerides, very low-density lipoprotein (VLDL)-C, and large LDL (LDL1-C) levels as well as mean LDL particle size (all p < 0.020). However, no significant difference was observed in total cholesterol, LDL-C, or apoB levels by CETP variants. Regardless of sex, the combination of rs3764261 (CC genotype) and rs708272 (GG or GA genotypes) showed a stronger association with atherogenic dyslipidemia, including features of decreased HDL-C, elevated triglycerides, and LDL subclass pattern B (odds ratio [OR] = 2.99, 95% confidence interval [CI]: 1.78-5.02) compared with the single variant rs3764261 (OR = 2.11, 95% CI: 1.27-3.50) or rs708272 (OR = 2.12, 95% CI: 1.29-3.49).ConclusionThe polymorphisms of CETP rs3764261 (CC genotype) and rs708272 (GG and GA genotypes) may have a higher susceptibility to atherogenic dyslipidemia. Testing for CETP rs3764261 and rs708272 may serve as a surrogate marker for lipid management in statin-treated patients, which may help individualize treatment for reducing the residual risk of ASCVD.

Project description:BackgroundOne of the major risk factors for cardiovascular disease is atherogenic dyslipidemia. There was, however, little information available in Ethiopia. Therefore, the purpose of this study was to estimate the prevalence of atherogenic dyslipidemia and related risk factors in Northeast Ethiopian hypertension patients.Materials and methodsA systematic random sampling technique was used to perform a cross-sectional study at an institution with 384 chosen participants. A structured questionnaire was used to collect the socio-demographic, anthropometric, lifestyle, and clinical characteristics of the respondents. Student's t-test, Mann-Whitney test, and Pearson's Chi-square test were employed to compare groups based on the type of data. Furthermore, Bivariate and multivariable logistic regression analyses were performed to identify factors independently associated with dyslipidemia. Crude and adjusted odds ratios and their corresponding 95% Confidence Intervals (CI) were computed. In all cases, statistical significance was declared at p <0.05.ResultsThe majority (93.2%; 95%CI: 90.6-95.6) of patients had at least one atherogenic dyslipidemia. The prevalence of elevated total cholesterol (TC), elevated triglyceride (TG), raised low-density lipoprotein cholesterol (LDL-c), and reduced high-density lipoprotein cholesterol (HDL-c) were 47.7%, 50.3%, 44.3%, and 59.6%, respectively. Being≥ 40 years were at higher risk for having elevated levels of TC (AOR: 3.22, 95% CI: 2.40-4.32), TG (AOR: 2.30, 95% CI: 1.61-3.79), and LDL-c (AOR: 4.68, 95% CI: 2.0-10.95) than those who were below 40years. Obese participants were more likely to have high concentrations of TC (AOR: 2.57, 95%CI: 2.10-3.22), LDL-c (AOR: 3.13, 95% CI: 1.97-5.10), HDL-c (AOR: 2.71, 95% CI: 1.77-4.58), and TG (AOR: 2.23, 95%CI: 1.79-4.16).ConclusionThis study revealed that a high prevalence of atherogenic dyslipidemia. Thus, to prevent atherogenic dyslipidemia, it is crucial to create routine blood lipid testing programs and carry out suitable intervention programs focused on risk factor reduction.

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

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<i>PCSK7</i> gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.

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