Haplotype of the Lipoprotein(a) Gene Variants Rs10455872 and Rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients After Myocardial Infarction and Highly Elevated Lipoprotein(a) Values

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jan 23

PMID 38255810

Authors

Sabina Ugovsek

Andreja Rehberger Likozar

Tina Levstek

Katarina Trebusak Podkrajsek

Janja Zupan

Miran Sebestjen

Affiliations

Soon will be listed here.

Abstract

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, = 0.046) and plasminogen activator inhibitor-1 (PAI-1) ( = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, = 0.038) and overall fibrinolytic potential (r = -0.253, = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.

References

Ansari W, Humphries S, Naveed A, Khan O, Khan D, Khattak E . Effect of Coronary Artery Disease risk SNPs on serum cytokine levels and cytokine imbalance in Premature Coronary Artery Disease. Cytokine. 2017; 122:154060. DOI: 10.1016/j.cyto.2017.05.013. View

Rehberger Likozar A, Blinc A, Trebusak Podkrajsek K, Sebestjen M . Genotypes and Haplotypes Are Associated with Lipoprotein(a) Levels but Not Arterial Wall Properties in Stable Post-Coronary Event Patients with Very High Lipoprotein(a) Levels. J Cardiovasc Dev Dis. 2021; 8(12). PMC: 8707421. DOI: 10.3390/jcdd8120181. View

German C, Liao J . Understanding the molecular mechanisms of statin pleiotropic effects. Arch Toxicol. 2023; 97(6):1529-1545. PMC: 10119541. DOI: 10.1007/s00204-023-03492-6. View

Simantiris S, Antonopoulos A, Papastamos C, Benetos G, Koumallos N, Tsioufis K . Lipoprotein(a) and inflammation- pathophysiological links and clinical implications for cardiovascular disease. J Clin Lipidol. 2022; 17(1):55-63. DOI: 10.1016/j.jacl.2022.10.004. View

Tsimikas S, Brilakis E, Miller E, McConnell J, Lennon R, Kornman K . Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005; 353(1):46-57. DOI: 10.1056/NEJMoa043175. View

Longstaff C . Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost. 2018; 16(4):652-662. PMC: 5947570. DOI: 10.1111/jth.13957. View

Pirro M, Bianconi V, Paciullo F, Mannarino M, Bagaglia F, Sahebkar A . Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial loss of integrity. Pharmacol Res. 2017; 119:178-187. DOI: 10.1016/j.phrs.2017.02.001. View

Clarke R, Hammami I, Sherliker P, Valdes-Marquez E, Watkins H, Hill M . Oxidized phospholipids on apolipoprotein B-100 versus plasminogen and risk of coronary heart disease in the PROCARDIS study. Atherosclerosis. 2022; 354:15-22. DOI: 10.1016/j.atherosclerosis.2022.06.1020. View

Kamstrup P, Tybjaerg-Hansen A, Steffensen R, Nordestgaard B . Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009; 301(22):2331-9. DOI: 10.1001/jama.2009.801. View

10.

Yahya R, Berk K, Verhoeven A, Bos S, van der Zee L, Touw J . Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype. Atherosclerosis. 2019; 289:201-205. DOI: 10.1016/j.atherosclerosis.2019.07.001. View

11.

Coassin S, Kronenberg F . Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene. Atherosclerosis. 2022; 349:17-35. PMC: 7613587. DOI: 10.1016/j.atherosclerosis.2022.04.003. View

12.

Clarke R, Peden J, Hopewell J, Kyriakou T, Goel A, Heath S . Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009; 361(26):2518-28. DOI: 10.1056/NEJMoa0902604. View

13.

He S, Bremme K, Blomback M . A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res. 1999; 96(2):145-56. DOI: 10.1016/s0049-3848(99)00092-4. View

14.

Salari N, Morddarvanjoghi F, Abdolmaleki A, Rasoulpoor S, Khaleghi A, Afshar Hezarkhani L . The global prevalence of myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2023; 23(1):206. PMC: 10122825. DOI: 10.1186/s12872-023-03231-w. View

15.

van der Valk F, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul J . Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation. 2016; 134(8):611-24. PMC: 4995139. DOI: 10.1161/CIRCULATIONAHA.116.020838. View

16.

Willeit P, Ridker P, Nestel P, Simes J, Tonkin A, Pedersen T . Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018; 392(10155):1311-1320. DOI: 10.1016/S0140-6736(18)31652-0. View

17.

Kamstrup P, Benn M, Tybjaerg-Hansen A, Nordestgaard B . Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation. 2007; 117(2):176-84. DOI: 10.1161/CIRCULATIONAHA.107.715698. View

18.

Scipione C, McAiney J, Simard D, Bazzi Z, Gemin M, Romagnuolo R . Characterization of the I4399M variant of apolipoprotein(a): implications for altered prothrombotic properties of lipoprotein(a). J Thromb Haemost. 2017; 15(9):1834-1844. DOI: 10.1111/jth.13759. View

19.

Tsironis L, Mitsios J, Milionis H, Elisaf M, Tselepis A . Effect of lipoprotein (a) on platelet activation induced by platelet-activating factor: role of apolipoprotein (a) and endogenous PAF-acetylhydrolase. Cardiovasc Res. 2004; 63(1):130-8. DOI: 10.1016/j.cardiores.2004.03.005. View

20.

Bergmark C, Dewan A, Orsoni A, Merki E, Miller E, Shin M . A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008; 49(10):2230-9. DOI: 10.1194/jlr.M800174-JLR200. View