Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease

Li, Ziang; Zhang, Bin; Liu, Qingrong; Tao, Zhihang; Ding, Lu; Guo, Bo; Zhang, Erli; Zhang, Haitong; Meng, Zhen; Guo, Shuai; Chen, Yang; Jia, Peng; Li, Jinyue; Wang, Can; Huang, Yingbo; Xu, Huibi; Li, Ziang

doi:10.1016/j.ebiom.2023.104543

Cited by 61 publications

(25 citation statements)

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“…Considering the established impact of PCSK9 inhibition on LDL levels [35] , the selection of variants resembling PCSK9 proxies near the PCSK9 gene was based on LDL levels as a criterion. The utilization of a drug-targeted MR method has been extensively employed in prior published studies [17,19,[36][37][38] . In order to enhance the credibility of these SNPs, we employed the CHDdataset as a positive control and observed a signi cant decrease in risk of CHD associated with these SNPs, thus validating their suitability as IVs.…”

Section: Discussionmentioning

confidence: 99%

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PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from mendelian randomization, cohort studies and basic experiments

Xu,

Wang,

Wang

et al. 2024

Preprint

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Background Current evidences suggest that Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) exhibit a protective influence on acute coronary syndrome (ACS). Nevertheless, further investigation is required to comprehend the impact and mechanisms of these pharmaceutical agents on inflammatory factors and arterial stiffness (AS) in patients with ACS. Consequently, the objective of this study is to ascertain the influence of PCSK9i on arterial stiffness in ACS patients and elucidate the underlying mechanisms behind their actions. Methods This study employed Mendelian randomization (MR) analysis to examine the association between genetic prediction of PCSK9 inhibition and arterial stiffness. A total of 71 patients with ACS were randomly allocated into either a PCSK9i group or a control group. Blood lipid levels, inflammatory markers and pulse wave velocity (PWV) data were collected before treatment and at 1 and 6 months after treatment for analysis. Additionally, cell experiments were conducted to investigate the impact of PCSK9i on osteogenesis of vascular smooth muscle cells (VSMCs), utilizing western blot (WB), enzyme-linked immunosorbent assay (ELISA), and calcification index measurements. Results The results of the MR analysis suggest that genetic prediction of PCSK9 inhibition has potential to reduce the pulse wave reflection index (PWV). Following treatment of statins combined with PCSK9 inhibitors for 1 and 6 months, the PCSK9i group exhibited significantly lower levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen (FIB) and procalcitonin (PCT) compared to the control group (p < 0.05). Additionally, PWV in the PCSK9i group demonstrated significant reduction after 6 months of treatment and was found to be associated with the circulating CRP level. In cell experiments, PCSK9i pretreatment ameliorated osteogenesis of VSMCs through reducing the deposition of calcium ions, alkaline phosphatase (ALP) activity, and expression of runt-related transcription factor 2(RUNX2). Conclusion PCSK9i have potential to enhance arterial stiffness at various aspects, including the genetic, clinical, and cellular domains. Specifically, at the clinical level, this impact may be attributed to alterations in circulating CRP levels. At the cellular level, it is associated with the signaling pathway linked to RUNX2.

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Section: Discussionmentioning

confidence: 99%

“…Positive control and outcome dataset selection Based on previously researches [19] , we used coronary heart disease (CHD, ieu-a-7) data from the Consortium for the Genetics of Coronary Artery Disease (CARDIoGRAMplusC4D) [20] as a positive control dataset, comprising 60801 cases and 123504 controls.…”

Section: Methodsmentioning

confidence: 99%

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from mendelian randomization, cohort studies and basic experiments

Xu,

Wang,

Wang

et al. 2024

Preprint

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“…According to previous research, The most common drugs used to lower lipid levels were chosen, including HMG-CoA reductase inhibitors (statins), PCSK9 inhibitors, Antisense oligonucleotide, targeting ApoB-100 mRNA and Antisense oligonucleotide targeting ApoC-III mRNA [10,11] (Table 1). These drug-target gene thresholds were identi ed at the website (https://www.ncbi.nlm.nih.gov/gene).…”

Section: Selection Of Instrumental Variablesmentioning

confidence: 99%

“…Instrumental variables that proxy for these drug target genes were selected within 100 ± kb of the corresponding genes [11,12], where instrumental variables with a signi cance level (p-value) less than 5×10 − 8 were deemed to be strongly associated with the genes targeted by the drug. To avoid the effect of LD on the results, the LD Aggregation threshold(r2 < 0.1)and physical distance threshold (250 kb) were taken.…”

Section: Selection Of Instrumental Variablesmentioning

confidence: 99%

Association of lipids and lipid-lowering drug target genes with Osteomyelitis : A mendelian randomization analysis

Zhou,

Yang,

Chen

et al. 2024

Preprint

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Background: Studies have shown that lipid metabolism is a key regulator of inflammation in acute and chronic conditions. However, it is currently unclear whether dyslipidemia is related to the process of osteomyelitis. To explore the link between lipid characteristics and osteomyelitis, our study used MR analysis to explore the link between triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and osteomyelitis. Besides, the link between the gene targets corresponding to these traits and osteomyelitis was further explored. Method: Genetic variants associated with TG and TC are selected from the Global Lipids Genetics Consortium, while LDL-C datasets were extracted from UK Biobank. Osteomyelitis was identified in FinnGen consortium (R10). The lipid-lowering drug targets showing significance were additionally assessed using the inflammatory response marker C-reactive protein (CRP). Furthermore, mediation analyses were performed to validate the reliability of the findings and explore potential mediating factors. Result: No association was found between LDL-C, TG, or TC and osteomyelitis. Proprotein convertase subtilisin/kexin type 9(PCSK9) was significantly associated with lower osteomyelitis risk in the dataset(OR [95%Cl] = 0.49[0.32 to 0.76], p = 1.60×10 − 3). PCSK9 was significantly associated with lower CRP risk(OR [95%Cl] = 0.94[0.92 to 0.97], p = 3.16×10 − 4). Our results support waist circumference as an intermediate variable between PCSK9 and osteomyelitis. Conclusion: This study does not support the relationship between dyslipidemia and osteomyelitis. PCSK9 was found to be significantly associated with a lower risk of osteomyelitis. Our study supports that waist circumference may be a potential mediator between osteomyelitis and PCSK9. In addition, we found that PCSK9 showed a reduction in CRP levels.

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“…Protein-protein interaction (PPI) network are composed of proteins that participate in various aspects of life processes such as biological signalling, regulation of gene expression, energy and material metabolism, and cell cycle regulation through interactions with each other 48 . In this study, a preliminary exploration of PPI network was carried out by combining signi cant MRPs obtained after a rigorous screening process with some drug-targeting proteins previously reported in the literature as potentially acting in NAFLD [49][50][51][52][53][54][55] .All PPI analyses were conducted using the Search Tool for the Retrieval of Interacting Genes (STRING) (https://string-db.org/ )database (version 11.5.0), with the minimum required interaction score at 0.4.0.The resultant le was imported into Cytoscape (version 3.9.0) for visualization 56 .…”

Section: Protein-protein Interaction Networkmentioning

confidence: 99%

Assessing the causal relationship between mitochondria-associated proteins and chronic liver diseases：a comprehensive Mendelian randomisation study

guo,

Ye,

Wang

et al. 2023

Preprint

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Mitochondria-related proteins (MRPs) and chronic liver diseases have been linked in various studies, although their causal relationship has not been elucidated. In this study, we investigated the causal associations between MRPs and non-alcoholic fatty liver disease (NALFD), liver cirrhosis and hepatocellular carcinoma (HCC) by two-sample bidirectional Mendelian randomisation(MR) analysis.The random-effect Inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and Weighted Median (WM) as complementary analyses. Cochran Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out analysis were used for sensitivity analyses. In addition, we performed bonferroni correction,multivariable MR analysis(MVMR),reverse causality detection and protein–protein interaction(PPI) network to enrich the results of this study.After rigorous genetic variant selection, IVW, sensitivity analysis, 3 genetically determined MRPs were significantly associated with NAFLD [MRPL33 (OR: 1.06, 95% CI: 1.00-1.11, p = 0.0284), MRPL34 (OR: 0.88, 95% CI: 0.78–0.98, p = 0.0294) and FARS2 (OR : 0.90, 95% CI: 0.84–0.97, p = 0.0120)], 2 MRPs were significantly associated with liver cirrhosis[MICU1 (OR: 1.11, 95% CI: 1.00-1.22, p = 0.0337) and NUDT8 (OR: 1.16, 95% CI: 1.03–1.30, p = 0.0096)], and 4 MRPs were significantly correlated with HCC [MRPL32 (OR: 0.62, 95% CI: 0.39–0.99, p = 0. 0492), MRPL33 (OR:1.29, 95% CI: 1.07–1.55, p = 0.0063), SCO1 (OR:0.56, 95% CI. 0.38–0.83, p = 0.0036) and SIRT5 (OR:0.71, 95% CI: 0.53–0.96, p = 0.0283)].Our findings provide a new perspective on the exploration of the underlying mechanisms of chronic liver diseases. However, further studies are still needed to explore the mechanisms of possible potential causal associations between MRPs and chronic liver diseases.

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Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease

Cited by 61 publications

References 50 publications

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from mendelian randomization, cohort studies and basic experiments

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from mendelian randomization, cohort studies and basic experiments

Association of lipids and lipid-lowering drug target genes with Osteomyelitis : A mendelian randomization analysis

Assessing the causal relationship between mitochondria-associated proteins and chronic liver diseases：a comprehensive Mendelian randomisation study

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