Lipoprotein(a), ABO Blood Types and Clinical Outcomes: Novel Findings and Clinical Implications in Patients With Chronic Coronary Syndrome

Abstract

This study aimed to investigate the effect of lipoprotein(a) (Lp(a)) on major adverse cardiovascular events (MACEs) among individuals with chronic coronary syndrome (CCS) according to ABO blood groups. Two independent cohorts of patients with CCS were included consecutively. Blood groups and Lp(a) levels were measured. Patients with the AB group were excluded due to the small sample size. In the exploratory cohort (n = 7611), 560 MACEs were recorded over a mean follow-up of 54.80 months. Stratification analysis revealed that the relationship of elevated Lp(a) levels with prognosis was more pronounced in patients with blood group A or B. Patients with blood group A or B plus medium Lp(a) (HR, 1.93, 95% CI: 1.24–3.01) or high Lp(a) (HR, 2.06, 95% CI: 1.32–3.24) concentrations had a significantly higher risk of MACEs compared to those with blood group O and low Lp(a) levels. Similar results were obtained in the confirmatory cohort (n = 7916). In conclusion, our data demonstrated for the first time a more prominent association between Lp(a) and adverse outcomes in CCS patients with non-O blood group compared to those with blood group O, suggesting that ABO blood group measurement may be clinically useful for decision-making in Lp(a) intervention.

Keywords

blood group / chronic coronary syndrome / lipoprotein(a) / outcome

References

[1] S. B. Abegaz, “Human ABO Blood Groups and Their Associations With Different Diseases,” BioMed Research International 2021 (2021): 6629060.

[2] M. C. van Schie, J. E. van Loon, M. P. de Maat, et al., “Genetic Determinants of von Willebrand Factor Levels and Activity in Relation to the Risk of Cardiovascular Disease: A Review,” Journal of Thrombosis and Haemostasis 9, no. 5 (2011): 899–908.

[3] C. Carpeggiani, M. Coceani, P. Landi, et al., “ABO Blood Group Alleles: A Risk Factor for Coronary Artery Disease. An Angiographic Study,” Atherosclerosis 211, no. 2 (2010): 461–466.

[4] P. Gong, S. H. Luo, X. L. Li, et al., “Relation of ABO Blood Groups to the Severity of Coronary Atherosclerosis: An Gensini Score Assessment,” Atherosclerosis 237, no. 2 (2014): 748–753.

[5] H. E. Groot, L. E. Villegas Sierra, M. A. Said, et al., “Genetically Determined ABO Blood Group and Its Associations With Health and Disease,” Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 3 (2020): 830–838.

[6] J. Hoglund, T. Karlsson, T. Johansson, et al., “Characterization of the Human ABO Genotypes and Their Association to Common Inflammatory and Cardiovascular Diseases in the UK Biobank,” American Journal of Hematology 96, no. 11 (2021): 1350–1362.

[7] M. He, B. Wolpin, K. Rexrode, et al., “ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort Studies,” Arteriosclerosis, Thrombosis, and Vascular Biology 32, no. 9 (2012): 2314–2320.

[8] A. Amirzadegan, M. Salarifar, S. Sadeghian, et al., “Correlation Between ABO Blood Groups, Major Risk Factors, and Coronary Artery Disease,” International Journal of Cardiology 110, no. 2 (2006): 256–258.

[9] P. Gong, S. Li, S. H. Luo, et al., “High-Sensitivity C-Reactive Protein Mediates in Part the Impact of ABO Blood Group on Coronary Artery Disease,” International Journal of Cardiology 177, no. 2 (2014): 641–643.

[10] T. R. Ketch, S. J. Turner, M. T. Sacrinty, et al., “ABO Blood Types: Influence on Infarct Size, Procedural Characteristics and Prognosis,” Thrombosis Research 123, no. 2 (2008): 200–205.

[11] G. L. Daniels, A. Fletcher, G. Garratty, et al., “Blood Group Terminology 2004: From the International Society of Blood Transfusion committee on Terminology for Red Cell Surface Antigens,” Vox Sanguinis 87, no. 4 (2004): 304–316.

[12] M. P. Reilly, M. Li, J. He, et al., “Identification of ADAMTS7 as a Novel Locus for Coronary Atherosclerosis and Association of ABO With Myocardial Infarction in the Presence of Coronary Atherosclerosis: Two Genome-Wide Association Studies,” Lancet 377, no. 9763 (2011): 383–392.

[13] O. Wu, N. Bayoumi, M. A. Vickers, et al., “ABO(H) Blood Groups and Vascular Disease: A Systematic Review and Meta-Analysis,” Journal of Thrombosis and Haemostasis 6, no. 1 (2008): 62–69.

[14] P. V. Jenkins and J. S. O'Donnell, “ABO Blood Group Determines Plasma von Willebrand Factor Levels: A Biologic Function After All?,” Transfusion 46, no. 10 (2006): 1836–1844.

[15] D. I. Chasman, G. Pare, S. Mora, et al., “Forty-Three Loci Associated With Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis,” PLos Genetics 5, no. 11 (2009): e1000730.

[16] S. Kiechl, G. Pare, M. Barbalic, et al., “Association of Variation at the ABO Locus With Circulating Levels of Soluble Intercellular Adhesion Molecule-1, Soluble P-Selectin, and Soluble E-Selectin: A Meta-Analysis,” Circulation: Cardiovascular Genetics 4, no. 6 (2011): 681–686.

[17] S. Tsimikas and S. M. Marcovina, “Ancestry, Lipoprotein(a), and Cardiovascular Risk Thresholds: JACC Review Topic of the Week,” Journal of the American College of Cardiology 80, no. 9 (2022): 934–946.

[18] W. J. Loh, X. Chang, T. C. Aw, et al., “Lipoprotein(a) as Predictor of Coronary Artery Disease and Myocardial Infarction in a Multi-Ethnic Asian Population,” Atherosclerosis 349 (2022): 160–165.

[19] H. H. Liu, Y. X. Cao, J. L. Jin, et al., “Predicting Cardiovascular Outcomes by Baseline Lipoprotein(a) Concentrations: A Large Cohort and Long-Term Follow-Up Study on Real-World Patients Receiving Percutaneous Coronary Intervention,” Journal of the American Heart Association 9, no. 3 (2020): e014581.

[20] A. Langsted, B. G. Nordestgaard, and P. R. Kamstrup, “Elevated Lipoprotein(a) and Risk of Ischemic Stroke,” Journal of the American College of Cardiology 74, no. 1 (2019): 54–66.

[21] K. Schmidt, A. Noureen, F. Kronenberg, et al., “Structure, Function, and Genetics of Lipoprotein (a),” Journal of Lipid Research 57, no. 8 (2016): 1339–1359.

[22] J. L. Jin, Y. X. Cao, H. W. Zhang, et al., “Lipoprotein(a) and Cardiovascular Outcomes in Coronary Artery Disease Patients With Prediabetes and Diabetes,” Diabetes Care 42 (2019): 1312–1318.

[23] P. R. Kamstrup, A. Tybjaerg-Hansen, R. Steffensen, et al., “Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction,” Jama 301, no. 22 (2009): 2331–2339.

[24] H. H. Liu, Y. X. Cao, J. L. Jin, et al., “Association of Lipoprotein(a) Levels With Recurrent Events in Patients With Coronary Artery Disease,” Heart 106, no. 16 (2020): 1228–1235.

[25] H. H. Liu, Y. X. Cao, J. L. Jin, et al., “Lipoprotein (a), Hypertension, and Cardiovascular Outcomes: A Prospective Study of Patients With Stable Coronary Artery Disease,” Hypertension Research 44, no. 9 (2021): 1158–1167.

[26] W. Zhang, J. L. Speiser, F. Ye, et al., “High-Sensitivity C-Reactive Protein Modifies the Cardiovascular Risk of Lipoprotein(a): Multi-Ethnic Study of Atherosclerosis,” Journal of the American College of Cardiology 78, no. 11 (2021): 1083–1094.

[27] R. Puri, S. E. Nissen, B. J. Arsenault, et al., “Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease: A Prespecified Secondary Analysis of the ACCELERATE Trial,” JAMA Cardiology 5, no. 10 (2020): 1136–1143.

[28] A. Mehta, S. S. Virani, C. R. Ayers, et al., “Lipoprotein(a) and Family History Predict Cardiovascular Disease Risk,” Journal of the American College of Cardiology 76, no. 7 (2020): 781–793.

[29] G. Reyes-Soffer and M. Westerterp, “Beyond Lipoprotein(a) Plasma Measurements: Lipoprotein(a) and Inflammation,” Pharmacological Research 169 (2021): 105689.

[30] S. E. Ward, J. M. O'Sullivan, and J. S. O'Donnell, “The Relationship Between ABO Blood Group, von Willebrand Factor, and Primary Hemostasis,” Blood 136, no. 25 (2020): 2864–2874.

[31] S. Tsimikas, “A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies,” Journal of the American College of Cardiology 69, no. 6 (2017): 692–711.

[32] S. K. Vasan, K. Rostgaard, A. Majeed, et al., “ABO Blood Group and Risk of Thromboembolic and Arterial Disease: A Study of 1.5 Million Blood Donors,” Circulation 133, no. 15 (2016): 1449–1457. Discussion 1457.

[33] N. B. Larson, E. J. Bell, P. A. Decker, et al., “ABO Blood Group Associations With Markers of Endothelial Dysfunction in the Multi-Ethnic Study of Atherosclerosis,” Atherosclerosis 251 (2016): 422–429.

[34] F. Duarte Lau and R. P. Giugliano, “Lipoprotein(a) and Its Significance in Cardiovascular Disease: A Review,” JAMA Cardiology 7, no. 7 (2022): 760–769.

[35] J. J. Li, C. S. Ma, D. Zhao, et al., “Lipoprotein(a) and Cardiovascular Disease in Chinese Population: A Beijing Heart Society Expert Scientific Statement,” JACC Asia 2, no. 6 (2022): 653–665.

[36] F. Gragnano, F. Fimiani, M. Di Maio, et al., “Impact of Lipoprotein(a) Levels on Recurrent Cardiovascular Events in Patients With Premature Coronary Artery Disease,” Internal and Emergency Medicine 14, no. 4 (2019): 621–625.

[37] J. Zhou, X. Cui, X. Jin, et al., “Association Between Lipoprotein (a) Level on Admission and the Incidence of Subsequent Cardiovascular Events in Patients With Acute Coronary Syndrome,” International Journal of Cardiology 158, no. 3 (2012): 464–466.

[38] C. Lamina and N. C. Ward, “Lipoprotein (a) and Diabetes Mellitus,” Atherosclerosis 349 (2022): 63–71.

[39] E. Tasdighi, R. Adhikari, O. Almaadawy, et al., “LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics,” Annual Review of Pharmacology and Toxicology 64 (2024): 135–157.

[40] S. E. Nissen, W. Ni, X. Shen, et al., “Lepodisiran—A Long-Duration Small Interfering RNA Targeting Lipoprotein(a),” New England Journal of Medicine 392, no. 17 (2025): 1673–1683.

[41] N. R. Cook, S. Mora, and P. M. Ridker, “Lipoprotein(a) and Cardiovascular Risk Prediction Among Women,” Journal of the American College of Cardiology 72, no. 3 (2018): 287–296.

[42] M. S. Teng, L. A. Hsu, S. Wu, et al., “Mediation Analysis Reveals a Sex-Dependent Association Between ABO Gene Variants and TG/HDL-C Ratio That Is Suppressed by sE-selectin Level,” Atherosclerosis 228, no. 2 (2013): 406–412.

[43] K. H. Orstavik, P. Magnus, H. Reisner, et al., “Factor VIII and Factor IX in a Twin Population. Evidence for a Major Effect of ABO Locus on Factor VIII Level,” American Journal of Human Genetics 37, no. 1 (1985): 89–101.

[44] D. J. Bowen, “An Influence of ABO Blood Group on the Rate of Proteolysis of von Willebrand Factor by ADAMTS13,” Journal of Thrombosis and Haemostasis 1, no. 1 (2003): 33–40.

[45] S. Lampsas, M. Xenou, E. Oikonomou, et al., “Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment,” Molecules 28, no. 3 (2023): 969.

[46] E. I. Holthuis, F. L. J. Visseren, M. L. Bots, et al., “Risk Factor Clusters and Cardiovascular Disease in High-Risk Patients: The UCC-SMART Study,” Glob Heart 16, no. 1 (2021): 85.

[47] R. W. Gifford, “The Role of Multiple Risk Factors in Cardiovascular Morbidity and Mortality,” Cleveland Clinic Journal of Medicine 60, no. 3 (1993): 211–218.

[48] S. A. E. Peters, X. Wang, T. H. Lam, et al., “Clustering of Risk Factors and the Risk of Incident Cardiovascular Disease in Asian and Caucasian Populations: Results From the Asia Pacific Cohort Studies Collaboration,” BMJ Open 8, no. 3 (2018): e019335.

[49] J. J. Li, S. P. Zhao, D. Zhao, et al., “2023 Chinese Guideline for Lipid Management,” Frontiers in pharmacology 14 (2023): 1190934.

[50] T. J. Anderson, J. Gregoire, G. J. Pearson, et al., “2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult,” Canadian Journal of Cardiology 32, no. 11 (2016): 1263–1282.

[51] SCORE2 Working Group and ESC Cardiovascular Risk Collaboration. SCORE2 Risk Prediction Algorithms: New Models to Estimate 10-Year Risk of Cardiovascular Disease in Europe. European Heart Journal 42 25 (2021): 2439–2454.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.