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Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

ABSTRACT: The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR?=?2.50 95% CI 1.45-4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff?=?15.08 [7.60-22.57] p?=?0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR?=?3.88; 95% CI 1.582-9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.

SUBMITTER: Barbieri M

PROVIDER: S-EPMC3747137 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

Barbieri Michelangela M Esposito Antonietta A Angellotti Edith E Rizzo Maria Rosaria MR Marfella Raffaele R Paolisso Giuseppe G

PloS one 20130819 8

The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabo ...[more]

PMID: 23977033

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Project description:BackgroundSome observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD.MethodsGenetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators.FindingsNo significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1 = 0.60 [95% CI 0.50-0.72], p1 = 2.07 × 10-8; OR2 = 0.57 [95% CI 0.39-0.82], p2 = 3.00 × 10-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 10-3) and strong colocalisation association (PP.H4 = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk.InterpretationOur findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects.FundingCapital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).

Project description:BackgroundInflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive.ObjectiveThis study aimed to evaluate the association between inflammatory cytokines and NAFLD.MethodsPubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out.ResultsThe search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis.ConclusionsOur results indicated that increased CRP, IL-1β, IL-6, TNF-α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.

Dataset Information

Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

Publications

Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.

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