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Causal relationship between circulating inflammatory proteins and atherosclerosis: a bidirectional Mendelian

Bin Xu¹, Qiyang Xu¹, Yi Wang²

¹Department of Vascular Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang Province, China.

Journal of Cardiology

|May 8, 2025

Insights

This study used Mendelian randomization to link circulating inflammatory proteins (CIPs) to atherosclerosis (AS). Specific proteins like artemin and TNF increase AS risk, while others like IL-8 and IL-6 show protective effects, suggesting new therapeutic targets.

Area of Science:

Cardiovascular Research
Genetics
Immunology

Background:

Atherosclerosis (AS) is a major cause of cardiovascular disease, driven by chronic inflammation.
The precise links between circulating inflammatory proteins (CIPs) and distinct AS subtypes are not fully understood.

Purpose of the Study:

To investigate the causal relationships between CIPs and various atherosclerosis phenotypes using Mendelian randomization (MR).
To identify potential biomarkers and therapeutic targets for different forms of AS.

Main Methods:

Utilized genome-wide association study (GWAS) summary statistics from 14,824 European individuals.
Employed inverse variance weighted (IVW) MR analysis, with sensitivity analyses for pleiotropy, heterogeneity, and reverse causality.
Conducted a meta-analysis to consolidate findings on CIPs and AS subtypes.

Main Results:

Elevated artemin, glial cell line-derived neurotrophic factor (hGDNF), and tumor necrosis factor (TNF) are associated with increased peripheral atherosclerosis (PA) risk.
Higher levels of CUB domain-containing protein 1, IL-8, monocyte chemoattractant protein-3, transforming growth factor-alpha, and TNF receptor superfamily member 9 are linked to decreased cerebral artery atherosclerosis risk.
Fibroblast growth factor 21 (FGF-21), hGDNF, and IL-22 receptor subunit alpha-1 (IL-22RA1) are associated with increased coronary artery atherosclerosis (COA) risk, while IL-13 and TNF-beta show protective effects.
C-X-C motif chemokine 6 (CXCL6) and hGDNF are risk factors for general atherosclerosis (AECCP), whereas IL-2 receptor subunit beta and IL-6 are protective.
CXCL6, FGF-21, IL-22RA1, and hGDNF increase overall AS risk, while IL-6 demonstrates a protective effect.

Conclusions:

Identified specific CIPs with significant causal roles in diverse forms of AS.
Findings highlight potential novel biomarkers and therapeutic targets for AS management.

Read full analysis

Abstract

Background:

Atherosclerosis (AS) is a chronic inflammatory disease that significantly contributes to cardiovascular morbidity and mortality. Despite extensive research efforts, the connections between circulating inflammatory proteins (CIPs) and different subtypes of AS remain poorly understood. This study aims to clarify these relationships through Mendelian randomization (MR) analysis.

Methods:

We utilized summary statistics from genome-wide association studies (GWAS) that included 14,824 European participants to analyze inflammatory protein levels, alongside data from the IEU GWAS database for AS phenotypes. Our primary approach for MR analysis was the inverse variance weighted method. To ensure the validity and robustness of the causal relationships, we conducted tests for pleiotropy and heterogeneity, as well as reverse MR analysis to assess the possibility of reverse causality. Finally, we performed a meta-analysis to consolidate and interpret our findings comprehensively.

Results:

Our MR analysis identified several significant associations: elevated artemin [odds ratio (OR) = 1.195], glial cell line-derived neurotrophic factor (hGDNF) (OR = 1.173), and tumor necrosis factor (TNF) (OR = 1.179) levels increased peripheral atherosclerosis (PA) risk; higher CUB domain-containing protein 1 (OR = 0.534), interleukin (IL)-8 (OR = 0.274), monocyte chemoattractant protein-3 (OR = 0.373), transforming growth factor-alpha (OR = 0.306), and tumor necrosis factor receptor superfamily member 9 (OR = 0.423) levels decreased cerebral artery atherosclerosis risk; fibroblast growth factor 21 (FGF-21) (OR = 1.122), hGDNF (OR = 1.108), and IL-22 receptor subunit alpha-1 (IL-22RA1) (OR = 1.235) levels were positively associated with coronary artery atherosclerosis (COA) risk; while IL-13 (OR = 0.909) and TNF-beta levels (OR = 0.954) were negatively associated with COA risk. C-X-C motif chemokine 6 levels (CXCL6) (OR = 1.353) and hGDNF (OR = 1.161) were identified as risk factors for atherosclerosis, excluding cerebral, coronary, and peripheral arterial disease (AECCP). In contrast, IL-2 receptor subunit beta levels (OR = 0.801) and IL-6 levels (OR = 0.788) were found to be protective factors for AECCP. Additionally, CXCL6 (OR = 1.261), FGF-21 (OR = 1.090), IL-22RA1 (OR = 1.127), and hGDNF (OR = 1.134) exhibited a risk effect against overall AS risk, while IL-6 (OR = 0.834) exhibited a protective effect against overall AS risk.

Conclusions:

This study identifies specific CIPs that have significant causal effects on various forms of AS through MR analysis. The findings suggest potential biomarkers and treatment targets for preventing and managing different manifestations of AS in clinical practice.

Keywords:

Atherosclerosis Circulating inflammatory protein Mendelian randomization Meta-analysis

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