Exploring the Effects of Antihypertensive and Lipid-Lowering Drugs on Inflammatory Cytokine Levels (MRDLT)

Mendelian Randomization Analysis of Drug Targets: Exploring the Impact of Antihypertensive and Lipid-Lowering Therapies on Inflammatory Cytokines

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Dyslipidemias; Inflammatory Response; Chronic Inflammation; Inflammatory Cytokines

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 250736

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population includes adult patients diagnosed with hypertension, coronary artery disease, or dyslipidemia. These participants have genome-wide data collected through genome-wide association studies (GWAS) and include measurements of inflammatory cytokines. The study focuses on the effect of drug interventions on inflammatory biomarkers.

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• Participants under the age of 18.
• 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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in IL-1β Levels Due to ACE Inhibitors	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）	Baseline to 12 months
Reduction in TNF-α Levels Due to ACE Inhibitors	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）	Baseline to 12 months
Reduction in CRP Levels Due to ACE Inhibitors	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）	Baseline to 12 months
Modulation of MCP-1 Levels Due to Statin Therapy	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）	Baseline to 12 months
Modulation of MIP-1α Levels Due to Statin Therapy	The primary outcome is the modulation of plasma levels of MIP-1α in patients treated with statins (HMG-CoA reductase inhibitors).（Unit: pg/mL）	Baseline to 12 months
Modulation of MIP-1β Levels Due to Statin Therapy	The primary outcome is the modulation of plasma levels of MIP-1β in patients treated with statins (HMG-CoA reductase inhibitors).（Unit: pg/mL）	Baseline to 12 months
Reduction in IL-1β Levels Due to PCSK9 Inhibitors	The primary outcome is the reduction in plasma levels of IL-1β in individuals exposed to PCSK9 inhibitors.（Unit: pg/mL）	Baseline to 12 months
Reduction in IL-6 Levels Due to PCSK9 Inhibitors	The primary outcome is the reduction in plasma levels of IL-6 in individuals exposed to PCSK9 inhibitors.（Unit: pg/m）	Baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Cardiovascular Events Due to Antihypertensive Therapy	The secondary outcome evaluates the reduction in cardiovascular events (e.g., myocardial infarction, stroke) linked to antihypertensive therapies such as ACEIs and ARBs.	Baseline to 24 months
Changes in LDL-C Levels Due to Statin Therapy	This outcome examines changes in LDL cholesterol (LDL-C) levels due to statin therapy.	Baseline to 24 months
Changes in HDL-C Levels Due to Statin Therapy	This outcome examines changes in HDL cholesterol (HDL-C) levels due to statin therapy.	Baseline to 24 months
Reduction in IL-1β Levels Due to PCSK9 Inhibitors	The secondary outcome measures the reduction in IL-1β levels linked to PCSK9 inhibitors.	Baseline to 24 months
Changes in Cardiometabolic Outcomes Due to PCSK9 Inhibitors	This secondary outcome measures changes in cardiometabolic outcomes, including changes in lipid levels and inflammatory cytokine profiles.	Baseline to 24 months

Collaborators and Investigators

• Sponsor: Guangzhou Institute of Respiratory Disease
• Collaborators: Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): September 11, 2024

Study Registration Dates

• First Submitted: September 29, 2024
• First Submitted That Met QC Criteria: September 29, 2024
• First Posted (Actual): October 2, 2024

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: PCSK9 Inhibitors; CRP; TNF-α; MCP-1; ARBs; Causal Inference; Genetic Association Studies; IL-1β; ACE Inhibitors; HMG-CoA Reductase Inhibitors; Mendelian Randomization; Antihypertensive Drugs; Lipid-Lowering Drugs; NPC1L1 Inhibitors; Inflammatory Pathways
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Lipid Metabolism Disorders; Inflammation; Dyslipidemias
• Other Study ID Numbers: YYKC-2021-01-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) including de-identified genome-wide association study (GWAS) data and inflammatory cytokine levels will be shared. The data will be made available to qualified researchers upon request, following appropriate approval.
• IPD Sharing Time Frame: The data will be available starting 6 months after publication and will be accessible for a period of 5 years.
• IPD Sharing Access Criteria: Researchers requesting access to the data will need to submit a detailed study proposal and obtain approval from the study's governing ethics board.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No