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Unraveling the Causal Links Between Immune Cells, Lipids, and Cardiovascular Diseases: Insights from Mendelian
Fengwei He1, Tian Yang2, Wentao Zhang2
1Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China.
Insights
Specific immune cell subtypes and lipid profiles significantly impact cardiovascular disease (CVD) risk. Identifying protective immune phenotypes and understanding immune-lipid interactions offers new therapeutic targets for CVD.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Genetics
Background:
- Cardiovascular diseases (CVD) are leading causes of death globally.
- The precise causal links between specific immune cell subtypes and CVD risk are not fully understood.
- Immune cell dysregulation is implicated in the pathogenesis of various CVDs like coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and ischemic stroke (IS).
Purpose of the Study:
- To investigate the causal associations between 731 immune cell subtypes and the risk of major cardiovascular diseases (CVDs) using Mendelian randomization (MR).
- To explore the mediating roles of lipid profiles (HDL, LDL, VLDL, triglycerides) in the relationship between immune cell traits and CVD risk.
- To identify potential therapeutic targets by highlighting specific immune cell phenotypes and immune-lipid interactions relevant to CVD.
Main Methods:
- Mendelian randomization (MR) analysis was employed using genetic variants associated with immune cell traits.
- Inverse variance weighted (IVW) method was used to assess the causal effects of immune cell subtypes on CVD risk.
- Pleiotropy and heterogeneity tests were conducted to ensure the robustness of the MR findings. Lipid profiles were analyzed as potential mediators.
Main Results:
- Specific immune cell phenotypes were causally associated with CVD risk: increased CD27 on unswitched memory B cells, CD28- DN T cells, and CX3CR1 on CD14- CD16+ monocytes increased risk.
- Conversely, CD28 on regulatory T cells (Tregs) and HLA DR++ monocytes exhibited protective effects against CVD.
- Lipid profiles mediated CVD risk, with high-density lipoprotein (HDL) being protective, while low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and triglycerides increased risk. LDL and triglycerides partially mediated the effect of CX3CR1+ monocytes on MI risk.
Conclusions:
- Immune cell subtypes and lipid profiles are significant determinants of cardiovascular disease (CVD) risk.
- Regulatory T cells and other protective immune phenotypes represent potential therapeutic targets for CVD.
- Targeted therapies focusing on immune-lipid interactions are promising for managing CVD, given the mediating role of lipids in immune-driven disease pathways.
Background And Aim:
Cardiovascular diseases (CVD), including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and ischemic stroke (IS), are major causes of morbidity and mortality worldwide. Immune cells play crucial roles in CVD, but causal links between immune cell subtypes and CVD risk remain unclear. This study used Mendelian randomization (MR) to investigate these associations.
Methods And Results:
Exposure data were analyzed with a P < 1 × 10-5 threshold, excluding linkage disequilibrium SNPs. MR of 731 immune cell types used the inverse variance weighted (IVW) method, with pleiotropy and heterogeneity tests. Lipid profiles (HDL, LDL, VLDL, triglycerides) were assessed as mediators.Increased CD27 on unswitched memory B cells, CD28- DN T cells, and CX3CR1 on CD14- CD16+ monocytes raised CVD risk, while CD28 on Tregs and HLA DR++ monocytes were protective. For CAD, CD24+ CD27+ %B cells and SSC-A on HLA DR+ NK cells were protective, with certain T cells increasing risk. Similar trends were observed for MI, AF, and IS. Reverse MR showed no CVD effects on these positive immune traits. Lipid profiles mediated CVD risk, with HDL protective and LDL, VLDL, and triglycerides increasing risk. Mediation analyses showed LDL and triglycerides partially mediated CX3CR1-monocyte effects on MI risk. Functional enrichment identified cytokine signaling and inflammation in CVD.
Conclusions:
Our findings highlight immune cell subtypes and lipid traits in CVD risk. Regulatory T cells and protective phenotypes are therapeutic targets, while LDL and triglycerides mediate immune-disease pathways, emphasizing immune-lipid interactions for targeted therapies.
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