Genetic association analysis of lipid-lowering drug target genes in chronic kidney disease

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

The impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject debate. This Mendelian randomization (MR) study aims to elucidate the potential effects drug targets CKD development. We extracted 11 genetic variants encoding drugs from published genome-wide association (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A analysis was conducted targeting these drug-related genes. risk designated as primary outcome, while estimated glomerular filtration rate (eGFR) blood urea nitrogen (BUN) were assessed secondary outcomes. Additionally, mediation performed utilizing 731 immune cell phenotypes identify mediators. meta-analysis revealed significant between ANGPTL3 inhibitors reduced (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists significantly linked an increased 1.11 [1.02-1.22]). Regarding outcomes, did not affect eGFR BUN levels. Mediation indicated that reduction in by mediated through modulation phenotype, specifically HLA-DR CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899). Through drug-targeted MR analysis, we identified causal relationship CKD. may represent promising candidate for treatment.

Language: Английский

Plasma proteins and coronary atherosclerosis: A Mendelian randomization study

Medicine, Journal Year: 2025, Volume and Issue: 104(8), P. e41549 - e41549

Published: Feb. 21, 2025

Coronary atherosclerosis (AS) is a complicated and severe chronic pathological process that contributes to the basis of various cardiovascular diseases, which causes serious challenge global healthcare system. AS underlying physiopathological mechanism. Despite recent advances in research biomarkers therapeutic targets for AS, there remain significant limitations current targeted therapies AS. This study utilizes Mendelian randomization analysis leverage genetic variations order identify plasma proteins with causal relationships coronary Utilizing publicly available genome-wide association datasets, 4907 were assessed as exposure factors, being outcome variable. The primary analytical method employed was inverse variance weighted approach ensure robustness accuracy relationships. In addition, verify reliability results, we several complementary methods, including median, randomization-Egger, mode, simple mode approaches, thoroughly assess heterogeneity pleiotropy findings. To results exclude potential biases, leave-one-out sensitivity performed. Twenty analyzed identified ( P < .05), combined multiple bioinformatic analyses; among them, fibronectin 1 key target. These findings may provide new theoretical future drug development strategies.

Language: Английский

Causal relationship between benign prostatic hyperplasia and prostate cancer: a bidirectional Mendelian randomization analysis

Postgraduate Medical Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Abstract Objective Our aim is to explore the relation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) from a genetic level utilizing Mendelian randomization (MR). Methods The IEU genome-wide association studies database was surveyed for single nucleotide polymorphisms (SNPs) associated with BPH, PCa, PCa (validation cohort). Single were subjected stringent quality control based on rigorous screening criteria. BPH risk evaluated using inverse-variance weighted method (IVW), MR-Egger, simple mode, median, mode. Horizontal pleiotropy of assessed MR-Egger intercept test, while heterogeneity Cochran’s Q test. Reverse causality by evaluating as exposure outcome. A validation used verify Results increased significantly genetically predicted (IVW: OR [95% CI] = 1.3849 × 107 [2330, 8.2294 1010], P 2.0814 10−4). In reverse MR analysis, also 1.0011 [1.0003, 1.0019], 0.0031). findings consistent analysis results cohort. Sensitivity analyses indicated presence but no horizontal pleiotropy. Conclusion study presents proof significant bidirectional causal relationship an PCa. Key message Three research questions three bullet points What already known this topic? Observational suggest controversial allows investigation variants instrumental variables (IVs). does add? How might affect research, practice, or policy? Recognizing men diagnosed may benefit more protocols.

Language: Английский