Figure 1
Overview of the study process using Mendelian Randomization (MR) to assess the causal relationships between immune cells, lipid profiles, and cardiovascular disease (CVD). Immune cells (exposure) affect lipid profiles (mediator), which in turn influence CVD outcomes (outcome). The Two-Step MR approach involves Step 1 (Direct Effect B) linking lipid profiles to CVD and Step 2 (Direct Effect A) linking immune cells to lipid profiles. The mediation effect is calculated as the product of these effects. Total and reverse MR analyses assess overall impact and causality, with sensitivity and enrichment analyses examining genetic factors.
Table 1
Characteristics of selected GWAS data.
| NAME | GWAS ID | SNPs | NCASE | NCONTROL | SAMPLE SIZE | POPULATION | PMID |
|---|---|---|---|---|---|---|---|
| Exposure | |||||||
| Immune cell | ebi-a-GCST90001391-- ebi-a-GCST90002121 | 18,622 | NA | NA | 2,309,119 | European | 32929287 |
| Mediation | |||||||
| HDL cholesterol | ieu-b-109 | 12,321,875 | NA | NA | 403,943 | European | 32203549 |
| LDL cholesterol | ieu-b-110 | 12,321,875 | NA | NA | 440,546 | European | 32203549 |
| VLDL cholesterol | met-d-VLDL_C | 12,321,875 | NA | NA | 115,078 | European | NA |
| Triglycerides | ieu-b-111 | 12,321,875 | NA | NA | 441,016 | European | 32203549 |
| Outcome | |||||||
| Cardiovascular disease | ebi-a-GCST90086055 | 14,485,079 | 15,009 | 41,628 | 56,637 | European | 33893285 |
| Coronary artery disease | ebi-a-GCST003116 | 8,597,751 | 42,096 | 361 | 141,217 | European | 26343387 |
| Myocardial infarction | ebi-a-GCST90018877 | 24,172,914 | 20,917 | 440,906 | 461,823 | European | 34594039 |
| ebi-a-GCST011364 | 10,290,368 | 14,825 | 2,680 | 395,795 | European | 33532862 | |
| ebi-a-GCST011365 | 8,106,745 | 14,825 | 44,000 | 395,795 | European | 33532862 | |
| Heart failure | ukb-d-HEARTFAIL | 9,858,439 | 1,405 | 359,789 | 361,194 | European | NA |
| Atrial fibrillation | ebi-a-GCST006414 | 33,519,037 | 60,620 | 970,216 | 1,030,836 | European | 30061737 |
| Ischemic stroke | ebi-a-GCST90018864 | 24,174,314 | 11,929 | 472,192 | 484,121 | European | 34594039 |
| ebi-a-GCST005843 | 7,537,579 | 34,217 | 406,111 | 440,328 | European | 29531354 |
Figure 2
Forest plot summarizing the MR analysis results for the association between different immune cell phenotypes (exposure) and various cardiovascular outcomes (CVD, coronary artery disease, myocardial infarction, atrial fibrillation, ischemic stroke). The table includes details such as the number of SNPs used (nsnp), method (Inverse variance weighted), p-value, false discovery rate (FDR), and odds ratio (OR) with 95% confidence intervals (CI). Statistically significant associations are highlighted, providing insights into the potential causal roles of specific immune cell types in cardiovascular diseases.
Figure 3
Forest plot summarizing MR analysis results for the association between lipid profiles (exposure) and various cardiovascular outcomes.
Figure 4
Forest plot of MR analysis showing associations between immune cell phenotypes (exposure) and lipid profiles (outcome) for different cardiovascular diseases.
Table 2
Mediation analysis of the causal effects of immune cell traits on cardiovascular disease via blood lipid traits.
| TRAITS OF IMMUNE CELL | TRAITS OF BLOOD LIPID | TRAITS OF DISEASE | TOTAL EFFECT | DIRECT EFFECT A | DIRECT EFFECT B | MEDIATION EFFECT | MEDIATED PROPORTION (%) |
|---|---|---|---|---|---|---|---|
| β(95% CI) | β(95% CI) | β(95% CI) | β(95% CI) | ||||
| CX3CR1 on CD 14- CD 16+ monocyte (Monocyte) | LDL cholesterol | Cardiovascular disease | 0.054 (0.016, 0.093) | 0.006 (0.001, 0.012) | 0.191 (0.072, 0.309) | 0.001 (0.001, 0.002) | 2.2% (0.225%, 4.17%) |
| CD28 on CD39+ CD4+(Treg) | LDL cholesterol | Coronary artery disease | 0.027 (0.007, 0.046) | –0.007 (–0.011, –0.002) | 0.520 (0.385, 0.655) | –0.003 (–0.006, –0.001) | –12.8% (–21.1%, –4.38%) |
| CX3CR1 on monocyte(Monocyte) | LDL cholesterol | Myocardial infarction (ebi-a-GCST90018877) | 0.040 (0.013, 0.067) | 0.006 (0.001, 0.011) | 0.488 (0.339, 0.637) | 0.003 (0.001, 0.005) | 7.26% (1.11%, 13.4%) |
| Triglycerides | 0.008 (0.002, 0.013) | 0.262 (0.189, 0.335) | 0.003 (0.001, 0.005) | 7.26% (1.11%, 13.4%) | |||
| CX3CR1 on monocyte(Monocyte) | LDL cholesterol | Myocardial infarction (ebi-a-GCST011364) | 0.036 (0.010, 0.062) | 0.006 (0.001, 0.011) | 0.552 (0.397, 0.707) | 0.003 (0.001, 0.006) | 9.2% (1.4%, 17%) |
| Triglycerides | 0.008 (0.002, 0.013) | 0.332 (0.246, 0.417) | 0.003 (0.001, 0.006) | 9.2% (1.4%, 17%) | |||
| CCR7 on naive CD8br (Maturation stages of T cell) | HDL cholesterol | Ischemic stroke | –0.037 (–0.064, –0.010) | –0.005 (–0.010, –0.001) | –0.093 (–0.142, –0.044) | 0.001 (0.001, 0.001) | –1.23% (–0.003%, –2.45%) |
Figure 5
Forest plot presenting MR results for associations between immune cell phenotypes and lipid profiles and cardiovascular diseases.
Panels A-E show odds ratios (OR) and 95% confidence intervals (CI) from multiple MR methods (MR-Egger, weighted median, inverse variance weighted, simple mode, weighted mode). Asterisks indicate significance.
(A) CX3CR1 on CD14+CD16+ monocytes: LDL cholesterol, cardiovascular disease.
(B) CD28 on CD39+ CD4+ T cells: LDL cholesterol, coronary artery disease.
(C) CX3CR1 on monocytes: LDL cholesterol, triglycerides, myocardial infarction (ebi-a-GCST90018877).
(D) CX3CR1 on monocytes: LDL cholesterol, triglycerides, myocardial infarction (ebi-a-GCST90018877).
(E) CCR7 on naive CD8+ T cells: HDL cholesterol, ischemic stroke.
nsnp = number of SNPs. Error bars represent 95% CI.
Figure 6
Enrichment analysis of genes linked to causal SNPs to reveal immune cell roles in cardiovascular disease. (A–E) Sankey diagrams and dot plots depicting the results of enrichment analysis for immune cell traits associated with CVD (A), CAD (B), MI (C), AF (D), and IS (E).