Causal association between immune cells and atherosclerosis: a Mendelian randomization study_West China Medical Journal

Authors：

LIU Yue ^1,2 , ZHANG Shumeng ^1,2 , LIU Yingzhi ^1,2 , LU Yuwen ^1,2 , CHEN Lingli ^1,3 ,  LI Jie ^1,2,4

1. School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
2. Hunan Provincial Key Laboratory of Traditional Chinese Medical Diagnostics, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
3. Hunan Provincial Key Laboratory of Pathogenic Biology in Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China;
4. Hunan Provincial Key Laboratory Breeding Base of Traditional Chinese Medicine Powder and Innovative Drugs, Changsha, Hunan 410208, P. R. China;

Corresponding author：

LI Jie, Email: 003290@hnucm.edu.cn

Keywords：

Immune cell traits; atherosclerosis; genome-wide association study; Mendelian randomization; causal association

DOI：

10.7507/1002-0179.202408253

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Objective To investigate the potential causal associations between 731 immune cell traits and atherosclerosis by Mendelian randomization (MR) analysis. Methods Using single nucleotide polymorphisms (SNPs) as instrumental variables, genome-wide association study (GWAS) summary statistics (GCST90001391 to GCST90002121) for 731 immune cell traits were obtained from the GWAS Catalog database, and the atherosclerosis dataset (finn-b-I9_CORATHER) was retrieved from the IEU database for MR analysis. The inverse variance weighted method, MR-Egger regression, weighted median, simple mode, and weighted mode approaches were employed to estimate the causal effects between the 731 immune cell traits and atherosclerosis, using odds ratio (OR) with 95% confidence interval (CI) as the effect size. Cochran Q test was used to assess heterogeneity. Horizontal pleiotropy was evaluated using the MR-Egger intercept test and the MR-PRESSO method. Leave-one-out analysis was conducted to examine the sensitivity of the causal estimates to individual SNPs. Results MR analysis revealed potential causal associations between 24 immune cell traits and atherosclerosis (P<0.05). Among them, human leucocyte antigen (HLA)-DR on plasmacytoid dendritic cells (DC) [OR=1.035, 95%CI (1.016, 1.054), P<0.001] and hematopoietic stem cell absolute count (HSCAC) [OR=1.049, 95%CI (1.021, 1.077), P<0.001] showed significant positive causal associations with atherosclerosis (P≤0.001), whereas CD86 on CD62L⁺ myeloid DC [OR=0.953, 95%CI (0.926, 0.981), P=0.001] exhibited a significant negative causal association with atherosclerosis (P≤0.001). The results of Cochran Q test, MR-Egger regression, and MR-PRESSO indicated P-values>0.05, suggesting no evidence of heterogeneity or horizontal pleiotropy in the causal estimates for these three immune cell traits. Reverse MR analysis, using the 24 immune cell traits as outcome variables, showed no evidence of causal association (P>0.05), supporting a unidirectional causal relationship from immune cells to atherosclerosis. Conclusion HLA-DR on plasmacytoid DC and HSCAC may serve as risk factors for atherosclerosis, while CD86 on CD62L⁺ myeloid DC may play a protective role against atherosclerosis.

Citation： LIU Yue, ZHANG Shumeng, LIU Yingzhi, LU Yuwen, CHEN Lingli, LI Jie. Causal association between immune cells and atherosclerosis: a Mendelian randomization study. West China Medical Journal, 2025, 40(8): 1271-1275. doi: 10.7507/1002-0179.202408253 Copy

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2.	Döring Y, van der Vorst EPC, Weber C. Targeting immune cell recruitment in atherosclerosis. Nat Rev Cardiol, 2024, 21(11): 824-840.
3.	Tian S, Wang Y, Wan J, et al. Co-stimulators CD40^-CD40L, a potential immune-therapy target for atherosclerosis: a review. Medicine (Baltimore), 2024, 103(14): e37718.
4.	Snijckers RPM, Foks AC. Adaptive immunity and atherosclerosis: aging at its crossroads. Front Immunol, 2024, 15: 1350471.
5.	Du Z, Guo S, Sun Y, et al. Causal relationships between dietary habits and five major mental disorders: a two-sample Mendelian randomization study. J Affect Disord, 2023, 340: 607-615.
6.	Li W, Zhou Q, Zhou L, et al. Causal role of immune cell phenotypes in idiopathic sudden sensorineural hearing loss: a bi-directional Mendelian randomization study. Front Neurol, 2024, 15: 1368002.
7.	Chen Z, Guo Y, Sun H, et al. Exploration of the causal associations between circulating inflammatory proteins, immune cells, and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study and mediation analysis. Front Aging Neurosci, 2024, 16: 1394738.
8.	Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
9.	Sidore C, Busonero F, Maschio A, et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet, 2015, 47(11): 1272-1281.
10.	Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
11.	Tao T, Tang A, Lv L, et al. Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses. Front Immunol, 2024, 15: 1270401.
12.	He C, Kim HI, Park J, et al. The role of immune cells in different stages of atherosclerosis. Int J Med Sci, 2024, 21(6): 1129-1143.
13.	Yang J, Lin W, Ma Y, et al. Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study. Front Immunol, 2024, 15: 1370831.
14.	Khan FU, Khongorzul P, Raki AA, et al. Dendritic cells and their immunotherapeutic potential for treating type 1 diabetes. Int J Mol Sci, 2022, 23(9): 4885.
15.	Quirant-Sánchez B, Plans-Galván O, Lucas E, et al. HLA-DR expression on monocytes and sepsis index are useful in predicting sepsis. Biomedicines, 2023, 11(7): 1836.
16.	Lusta KA, Poznyak AV, Sukhorukov VN, et al. Hypotheses on atherogenesis triggering: does the infectious nature of atherosclerosis development have a substruction?. Cells, 2023, 12(5): 707.
17.	Gindri Dos Santos B, Goedeke L. Macrophage immunometabolism in diabetes-associated atherosclerosis. Immunometabolism (Cobham), 2023, 5(4): e00032.
18.	Chen X, Liu C, Wang J, et al. Hematopoietic stem cells as an integrative hub linking lifestyle to cardiovascular health. Cells, 2024, 13(8): 712.
19.	Meng Q, Liu H, Liu J, et al. Advances in immunotherapy modalities for atherosclerosis. Front Pharmacol, 2023, 13: 1079185.
20.	Piras L, Zuccanti M, Russo P, et al. Association between immune checkpoint inhibitors and atherosclerotic cardiovascular disease risk: another brick in the wall. Int J Mol Sci, 2024, 25(5): 2502.
21.	Baardman J, Lutgens E. Regulatory T cell metabolism in atherosclerosis. Metabolites, 2020, 10(7): 279.
22.	Hinkley H, Counts DA, VonCanon E, et al. T cells in atherosclerosis: key players in the pathogenesis of vascular disease. Cells, 2023, 12(17): 2152.
23.	Wang C, Zhu Y, Pan D. Identifying the causal relationship between immune factors and osteonecrosis: a two-sample Mendelian randomization study. Sci Rep, 2024, 14(1): 9371.

1. Borovac JA. The molecular mechanisms and therapeutic targets of atherosclerosis: from basic research to interventional cardiology. Int J Mol Sci, 2024, 25(9): 4936.
2. Döring Y, van der Vorst EPC, Weber C. Targeting immune cell recruitment in atherosclerosis. Nat Rev Cardiol, 2024, 21(11): 824-840.
3. Tian S, Wang Y, Wan J, et al. Co-stimulators CD40^-CD40L, a potential immune-therapy target for atherosclerosis: a review. Medicine (Baltimore), 2024, 103(14): e37718.
4. Snijckers RPM, Foks AC. Adaptive immunity and atherosclerosis: aging at its crossroads. Front Immunol, 2024, 15: 1350471.
5. Du Z, Guo S, Sun Y, et al. Causal relationships between dietary habits and five major mental disorders: a two-sample Mendelian randomization study. J Affect Disord, 2023, 340: 607-615.
6. Li W, Zhou Q, Zhou L, et al. Causal role of immune cell phenotypes in idiopathic sudden sensorineural hearing loss: a bi-directional Mendelian randomization study. Front Neurol, 2024, 15: 1368002.
7. Chen Z, Guo Y, Sun H, et al. Exploration of the causal associations between circulating inflammatory proteins, immune cells, and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study and mediation analysis. Front Aging Neurosci, 2024, 16: 1394738.
8. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
9. Sidore C, Busonero F, Maschio A, et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet, 2015, 47(11): 1272-1281.
10. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
11. Tao T, Tang A, Lv L, et al. Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses. Front Immunol, 2024, 15: 1270401.
12. He C, Kim HI, Park J, et al. The role of immune cells in different stages of atherosclerosis. Int J Med Sci, 2024, 21(6): 1129-1143.
13. Yang J, Lin W, Ma Y, et al. Investigation of the causal association between Parkinson’s disease and autoimmune disorders: a bidirectional Mendelian randomization study. Front Immunol, 2024, 15: 1370831.
14. Khan FU, Khongorzul P, Raki AA, et al. Dendritic cells and their immunotherapeutic potential for treating type 1 diabetes. Int J Mol Sci, 2022, 23(9): 4885.
15. Quirant-Sánchez B, Plans-Galván O, Lucas E, et al. HLA-DR expression on monocytes and sepsis index are useful in predicting sepsis. Biomedicines, 2023, 11(7): 1836.
16. Lusta KA, Poznyak AV, Sukhorukov VN, et al. Hypotheses on atherogenesis triggering: does the infectious nature of atherosclerosis development have a substruction?. Cells, 2023, 12(5): 707.
17. Gindri Dos Santos B, Goedeke L. Macrophage immunometabolism in diabetes-associated atherosclerosis. Immunometabolism (Cobham), 2023, 5(4): e00032.
18. Chen X, Liu C, Wang J, et al. Hematopoietic stem cells as an integrative hub linking lifestyle to cardiovascular health. Cells, 2024, 13(8): 712.
19. Meng Q, Liu H, Liu J, et al. Advances in immunotherapy modalities for atherosclerosis. Front Pharmacol, 2023, 13: 1079185.
20. Piras L, Zuccanti M, Russo P, et al. Association between immune checkpoint inhibitors and atherosclerotic cardiovascular disease risk: another brick in the wall. Int J Mol Sci, 2024, 25(5): 2502.
21. Baardman J, Lutgens E. Regulatory T cell metabolism in atherosclerosis. Metabolites, 2020, 10(7): 279.
22. Hinkley H, Counts DA, VonCanon E, et al. T cells in atherosclerosis: key players in the pathogenesis of vascular disease. Cells, 2023, 12(17): 2152.
23. Wang C, Zhu Y, Pan D. Identifying the causal relationship between immune factors and osteonecrosis: a two-sample Mendelian randomization study. Sci Rep, 2024, 14(1): 9371.

West China Medical Journal

Causal association between immune cells and atherosclerosis: a Mendelian randomization study

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