Mendelian Randomization Analysis of Drug Targets: Exploring the Impact of Antihypertensive and Lipid-Lowering Therapies on Inflammatory Cytokines
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 250,736
- 试验地点
- 1
- 主要终点
- Reduction in IL-1β Levels Due to ACE Inhibitors
研究概览
简要总结
This study investigates the causal relationships between antihypertensive and lipid-lowering drugs and inflammatory cytokines using a drug-targeted Mendelian randomization approach. By leveraging genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data, the study evaluates the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), HMG-CoA reductase inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors on key inflammatory cytokines such as IL-1β, TNF-α, CRP, and MCP-1. The findings aim to provide insights into the prevention and control of excessive inflammatory responses, particularly in patients with hypertension and dyslipidemia, by assessing the causal effects of these therapies.
详细描述
This observational study focuses on elucidating the causal relationships between commonly prescribed antihypertensive drugs (ACEIs and ARBs) and lipid-lowering drugs (HMG-CoA reductase inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors) with various inflammatory cytokines, including IL-1β, TNF-α, CRP, MCP-1, and IFN-γ, using a drug-targeted Mendelian randomization (MR) framework. The study employs large-scale genetic data from European populations, drawing from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) datasets, to construct instrumental variables that mimic the effects of drug exposure.
The primary aim is to explore how these pharmaceutical interventions influence inflammatory pathways at the molecular level. The use of MR methods enables causal inference by utilizing genetic variants within or near drug-target genes, allowing for the estimation of downstream effects similar to those produced by actual drug interventions. Key statistical methods, including inverse variance weighting and sensitivity analyses, are applied to ensure robustness and validity of the results.
This research provides critical evidence for the selection of antihypertensive and lipid-lowering therapies that not only manage cardiovascular risk factors but also modulate inflammation, contributing to personalized medicine strategies for patients with chronic inflammatory conditions. Furthermore, the findings have broader implications for drug repurposing and the development of new therapeutic targets aimed at mitigating inflammatory processes that underlie various chronic diseases.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants aged 18 years or older.
- •Diagnosed with hypertension, coronary artery disease, or dyslipidemia.
- •Availability of complete genome-wide data and inflammatory cytokine levels.
- •Willingness to participate in the study and provide the required clinical data.
排除标准
- •Participants under the age of
- •Individuals with severe chronic diseases or other conditions that may significantly influence inflammatory responses.
- •Individuals unwilling or unable to provide necessary clinical or genomic data.
- •Pregnant or breastfeeding women.
结局指标
主要结局
Reduction in IL-1β Levels Due to ACE Inhibitors
时间窗: Baseline to 12 months
The primary outcome is the reduction in plasma levels of IL-1β due to exposure to ACE inhibitors (ACEIs). The study evaluates the causal relationship between ACEIs and IL-1β levels using Mendelian randomization.（Unit: pg/mL）
Reduction in TNF-α Levels Due to ACE Inhibitors
时间窗: Baseline to 12 months
The primary outcome is the reduction in plasma levels of TNF-α due to exposure to ACE inhibitors (ACEIs). The study evaluates the causal relationship between ACEIs and TNF-α levels using Mendelian randomization.（Unit: pg/mL）
Reduction in CRP Levels Due to ACE Inhibitors
时间窗: Baseline to 12 months
The primary outcome is the reduction in plasma levels of CRP due to exposure to ACE inhibitors (ACEIs). The study evaluates the causal relationship between ACEIs and CRP levels using Mendelian randomization.（Unit: mg/L）
Modulation of MCP-1 Levels Due to Statin Therapy
时间窗: Baseline to 12 months
The primary outcome is the modulation of plasma levels of MCP-1 in patients treated with statins (HMG-CoA reductase inhibitors). The study investigates the effect of statins on MCP-1 levels.（Unit: pg/mL）
Modulation of MIP-1α Levels Due to Statin Therapy
时间窗: Baseline to 12 months
The primary outcome is the modulation of plasma levels of MIP-1α in patients treated with statins (HMG-CoA reductase inhibitors).（Unit: pg/mL）
Modulation of MIP-1β Levels Due to Statin Therapy
时间窗: Baseline to 12 months
The primary outcome is the modulation of plasma levels of MIP-1β in patients treated with statins (HMG-CoA reductase inhibitors).（Unit: pg/mL）
Reduction in IL-1β Levels Due to PCSK9 Inhibitors
时间窗: Baseline to 12 months
The primary outcome is the reduction in plasma levels of IL-1β in individuals exposed to PCSK9 inhibitors.（Unit: pg/mL）
Reduction in IL-6 Levels Due to PCSK9 Inhibitors
时间窗: Baseline to 12 months
The primary outcome is the reduction in plasma levels of IL-6 in individuals exposed to PCSK9 inhibitors.（Unit: pg/m）
次要结局
- Reduction in Cardiovascular Events Due to Antihypertensive Therapy(Baseline to 24 months)
- Changes in LDL-C Levels Due to Statin Therapy(Baseline to 24 months)
- Changes in HDL-C Levels Due to Statin Therapy(Baseline to 24 months)
- Reduction in IL-1β Levels Due to PCSK9 Inhibitors(Baseline to 24 months)
- Changes in Cardiometabolic Outcomes Due to PCSK9 Inhibitors(Baseline to 24 months)
研究者
Zhibin Xu
Professor
Guangzhou Institute of Respiratory Disease