Genetic association of lipid-lowering drug target genes with pancreatic cancer: a Mendelian randomization study

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 25, 2025

Previous studies have found that dyslipidemia is a risk factor for pancreatic cancer (PC), and lipid-lowering drugs may reduce the of PC. However, it not clear whether causes The Mendelian randomization (MR) study aimed to investigate causal role lipid traits in assess potential impact drug targets on cancer. Genetic variants associated with genes encoding were extracted from Global Lipids Genetics Consortium genome-wide association (GWAS). Summary statistics PC obtained an independent GWAS datasets. Colocalization analyses performed validate robustness results. No significant effect was found. mimicry lipoprotein lipase (LPL) potentially risks. Significant MR associations observed discovery dataset (OR 1.64 [95% CI 1.24–2.16], p = 4.48*10–4) one dataset. finding verified replication Our findings do support as Among targets, LPL target

Язык: Английский

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The role of lipids and lipids lowering drugs in human papillomavirus (HPV) and HPV-associated cancers

Infectious Agents and Cancer, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 28, 2025

Both women and men are now confronted with the grave threat of cancers caused by human papillomavirus (HPV). It is estimated that 80% may encounter HPV over their lives. In preponderance cases involving anal, head neck, oral, oropharyngeal, penile, vaginal, vulvar, cervical malignancies, high-risk (HR-HPV) causative agent. 2019, believed to have been cause 620,000 new cancer in 70,000 worldwide. The bulk 530,000 (~ 270,000 fatalities) infection (86% cases, 88% deaths) happen poor nations each year. Lipid metabolism crucial development related HPV. One most noticeable metabolic abnormalities lipid reprogramming, which cells dysregulate obtain sufficient energy, building blocks for cell membranes, signaling molecules necessary invasion, metastasis, proliferation, survival. Moreover, proteins' stimulation production infected will probably a significant effect on oncogenesis. addition, lipids critical producing cellular epithelial-mesenchymal transition (EMT) process, therapy resistance HPV-related (HRCs). Therefore, essential HRC also be an important target approaches associated treatments during or development. This review study looked at role lipid-lowering drugs cancers.

Язык: Английский

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Adverse Events Associated with Inclisiran: A Real-world pharmacovigilance study of FDA adverse event reporting system (FAERS)

Expert Opinion on Drug Safety, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

To gain an improved comprehension of inclisiran safety in real-world settings by data mining from the US Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). In a retrospective pharmacovigilance study, disproportionality analysis was utilized to determine AEs associated with use as signals. Data were gathered between 1 December 2020 31 2023. The Medical Dictionary for Regulatory Activities (MedDRA) corresponding preferred term (PT) system organ class (SOC) used categorize adverse medication reactions AE reports (AERs). By using reported odds ratio (ROR) method, positive signals identified. Clinical prioritization ranked semiquantitative score method based on three categories clinical significance. This performed assessing five distinct features: AER number, ROR value, mortality percentage, designated (DME) or important medical event (IME), biological plausibility. There 2,652 inclisiran, 150 those had significant signal. priority scores elucidated that 106 (70.67%), 44 (29.33%), 0 PTs classified weak, moderate, strong priorities, respectively. Among moderate priority, 35 discovered medicine label, including 12 IMEs 2 DMEs, such pancreatitis (DME, 3.29), deafness 2.10), myocardial Infarction (IME, 3.50), angina unstable 17.11), coronary artery occlusion 5.65), arrhythmia 2.15). Of note, 9 unanticipated label studies, movement disorder (ROR: 3.05; 95%CI: 1.73,5.37), aphonia 3.77; 1.79,7.91), pulmonary congestion 3.47; 1.44,8.34). Inclisiran found be related serious AEs, gait disturbance, hypertension, arthralgia, urinary tract infection, diabetes mellitus, dizziness, infarction, chest pain. median TTO 1896 cases 13.5 (IQR 0-100) days. Additionally, 39.72% (753/1896) occurred during first day post-inclisiran commencement. We identified not only known but also new disorder.However, does reveal actual risk, prospective trials are still required verify their causal connection.

Язык: Английский

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Reduction in Liver Cancer Risk by Quercetin via Modulation of Urate Levels: Insights from Drug-Target Mendelian Randomization

Genes, Год журнала: 2025, Номер 16(4), С. 449 - 449

Опубликована: Апрель 13, 2025

Background: Quercetin, a dietary flavonoid and widely used supplement, has hepatoprotective properties. Given its urate-lowering effects epidemiological evidence linking elevated serum urate levels to liver cancer risk, we tested whether quercetin reduces risk via modulation of by bioinformatics methods. Methods: We employed drug-target Mendelian randomization using genome-wide association study summary statistics from public databases (e.g., MRC-IEU) assess genetic associations, integrated these findings with GEO datasets (such as GSE138709 GSE179443) immune infiltration analyses tools like xCell, TIMER. Results: Our identified ABCG2-mediated elevation causal factor for hepatocellular carcinoma (OR = 1.001, p < 0.01), cholangiocarcinoma 3.424, fibrosis 2.528, 0.01). Single-cell transcriptomics revealed ABCG2 expression in endothelial cells, while analysis showed significant associations between both cell macrophage infiltration. Survival further indicated that was not associated poor prognosis or carcinoma. Conclusions: Considering quercetin’s multifaceted interactions BCRP/ABCG2, our support potential use preventive supplement hepatic diseases rather than an adjunctive therapy established cancer.

Язык: Английский

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The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies

Metabolites, Год журнала: 2024, Номер 14(7), С. 388 - 388

Опубликована: Июль 17, 2024

Atherosclerotic cardiovascular disease poses a significant global health issue, with dyslipidemia standing out as major risk factor. In recent decades, lipid-lowering therapies have evolved significantly, statins emerging the cornerstone treatment. These interventions play crucial role in both primary and secondary prevention by effectively reducing through lipid profile enhancements. Beyond their effects, extensive research indicates that these exhibit pleiotropic actions, offering additional benefits. include anti-inflammatory properties, improvements vascular glucose metabolism, potential implications cancer management. While ezetimibe been extensively studied, newer agents also demonstrate similar even absence of direct This narrative review explores diverse properties lipid-modifying therapies, emphasizing non-lipid effects contribute to burden exploring benefits for non-cardiovascular conditions. Mechanistic insights into actions are discussed alongside therapeutic implications.

Язык: Английский

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The Causal Relationship between PCSK9 Inhibitors and Osteoporosis Based on Drug-Targeted Mendelian Combined Mediation Analysis

Calcified Tissue International, Год журнала: 2024, Номер 115(1), С. 53 - 62

Опубликована: Май 24, 2024

PCSK9 inhibitors have been shown to lower serum low density lipoprotein cholesterol (LDL-C) levels and are considered integral in the treatment of cardiovascular diseases. However, potential association between osteoporosis is unclear now. In this study, drug-targeted mendelian randomization (MR) was utilized conjunction with mediation analysis including bone mineral (BMD), total 25-hydroxyvitamin D (T25(OH)D) calcium supplementation investigate causal relationship osteoporosis. The LDL-C level chosen as exposure variable a sample size 173,082 individuals. We conducted MR on osteoporosis, elucidating mediators involved. Utilizing inverse variance weighted (IVW) method, we found risk reduced by 0.6% those who used compared non-users (OR: 0.994, 95%CI: 0.991-0.998, P < 0.001). people aged 30-45 years, BMD 1.176 times higher among inhibitor users 1.176, 1.017-1.336, = 0.045). Conversely, 45-60 years had 14.9% 0.851, 0.732-0.968, 0.007). Mediation revealed that 43.33% impact mediated through levels, remaining 56.67% being direct effect. Effects varied different ages. addition, high T25(OH)D were 1.091 1.091, 1.065-1.112, 0.001), providing valuable insights for clinicians.

Язык: Английский

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Causal relationship between lipid-lowering drugs and ovarian cancer, cervical cancer: a drug target mendelian randomization study

BMC Cancer, Год журнала: 2024, Номер 24(1)

Опубликована: Май 31, 2024

Abstract Background The causal impact of lipid-lowering drugs on ovarian cancer (OC) and cervical (CC) has received considerable attention, but its relationship is still a subject debate. Hence, the objective this study to evaluate medications occurrence risk OC CC through Mendelian randomization (MR) analysis drug targets. Methods This investigation concentrated primary targets medications, specifically, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) proprotein convertase kexin 9 (PCSK9). Genetic variations associated with HMGCR PCSK9 were derived from published genome-wide association (GWAS) findings serve as substitutes for inhibitors. Employing MR approach, an was conducted scrutinize inhibitors targeting CC. Coronary heart disease (CHD) utilized positive control, outcomes encompassed Results suggest notable elevation in among patients treated (OR [95%CI] = 1.815 [1.316, 2.315], p 0.019). In contrast, no significant correlation observed between OC. Additionally, did not reveal any noteworthy connection inhibitors, Conclusion significantly elevate patients, their mechanism needs further investigation, influence been observed. There

Язык: Английский

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Comprehensive Mendelian randomization analysis of low-density lipoprotein cholesterol and multiple cancers

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 18, 2024

The aim of this study was to investigate the causal relationship between low-density lipoprotein cholesterol (LDL-C) and five cancers (breast, cervical, thyroid, prostate colorectal) using Mendelian Randomization (MR) method, with a view revealing potential role LDL-C in development these cancers.

Язык: Английский

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Lipids, lipid-lowering drug target genes and pancreatic cancer: a Mendelian randomization study

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июль 22, 2024

Background Pancreatic cancer (PC) is a malignant tumor with low survival rate. Lipid modifiers show potential for PC therapy, but evidence lacking. This Mendelian Randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes risk. Methods We used genetic instrumental variables associated traits conduct MR analyses estimation utilized genome-wide association (GWAS) data from two substantial sample sets, which were meta-analyzed evaluate their influence on To confirm reliability of modification targets, Summary Data-based (SMR) analysis was conducted. Additionally, two-step (TSMR) implemented investigate mediating roles. Result In Discovery Dataset, HMGCR inhibition statistically lower risk (OR = 0.46, [95% CI, 0.22–0.97]; p 0.0404), did not statistical significance in Replication result meta-analysis reached 0.50, 0.25-1.00]; 0.0453). The SMR enhanced robustness results 0.51, 0.28–0.96]; 0.0369). Furthermore, mediation revealed that lowering BMI levels mediated protective effect inhibitors (mediation effect: OR 0.91, CI,0.84–0.97], proportion:11.69%, 10.04%-13.61%]). Conclusions found significantly PC, suggesting has be candidate treatment or prevention PC.

Язык: Английский

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NR0B2 Is a Key Factor for Gastric Diseases: A GEO Database Analysis Combined with Drug-Target Mendelian Randomization

Genes, Год журнала: 2024, Номер 15(9), С. 1210 - 1210

Опубликована: Сен. 16, 2024

Small Heterodimer Partner (SHP; NR0B2) is an orphan receptor that acts as a transcriptional regulator, controlling various metabolic processes, and potential therapeutic target for cancer. Examining the correlation between expression of NR0B2 risk gastric diseases could open new path treatment drug development. The Gene Expression Omnibus (GEO) database was utilized to explore gene profiles in diseases. Co-expressed genes were identified through Weighted Correlation Network Analysis (WGCNA), GO enrichment performed identify pathways. Xcell method employed analyze immune infiltration relationships. To determine causal relationship diseases, we six single-nucleotide polymorphisms (SNPs) proxy located within 100 kilobases which are associated with triglyceride homeostasis drug-target Mendelian randomization (MR). Bioinformatics analysis revealed levels reduced cancer increased gastritis. Set Enrichment (GSEA) showed widely involved oxidation-related processes. Immune analyses found Treg. Prognostic low factor poor prognoses MR (NR0B2 vs. cancer, p = 0.006, OR: 0.073, 95%CI: 0.011–0.478; ulcer, 0.03, 0.991, 0.984–0.999; other gastritis, OR:3.82, 1.468–9.942). Our study confirms highlights its role progression present opens avenues exploring drugs either activate or inhibit

Язык: Английский

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