The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease

Abstract

Background The ABO locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the ABO risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants.

Methods We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the ABO locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential.

Results The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 − 1.09], p = 0.01) but not with clot lysis time (p = 0.97). The rs12936587 (p = 0.04), rs4773144 (p = 0.02), and rs501120 (p = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (p-values > 0.05).

Conclusion The ABO risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in ABO risk variant carriers.

Keywords

ABO blood-group system - blood coagulation - fibrin clot - fibrinolysis - coronary artery disease

• References

• 1 Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014; 114 (12) 1852-1866
• 2 Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis 2006; 186 (02) 240-259
• 3 Freynhofer MK, Bruno V, Wojta J, Huber K. The role of platelets in athero-thrombotic events. Curr Pharm Des 2012; 18 (33) 5197-5214
• 4 Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330 (15) 1041-1046
• 5 Nikpay M, Goel A, Won H-H. , et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47 (10) 1121-1130
• 6 Davies RW, Wells GA, Stewart AFR. , et al. A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex. Circ Cardiovasc Genet 2012; 5 (02) 217-225
• 7 Krarup NT, Borglykke A, Allin KH. , et al. A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals. Atherosclerosis 2015; 240 (02) 305-310
• 8 Christiansen MK, Nyegaard M, Larsen SB. , et al. A genetic risk score predicts cardiovascular events in patients with stable coronary artery disease. Int J Cardiol 2017; 241: 411-416
• 9 Reilly MP, Li M, He J. , et al; Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium. 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 2011; 377 (9763): 383-392
• 10 Christiansen MK, Larsen SB, Nyegaard M. , et al. The ABO locus is associated with increased platelet aggregation in patients with stable coronary artery disease. Int J Cardiol 2019; 286: 152-158
• 11 Neergaard-Petersen S, Ajjan R, Hvas A-M. , et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PLoS One 2013; 8 (08) e71150
• 12 Neergaard-Petersen S, Larsen SB, Grove EL, Kristensen SD, Ajjan RA, Hvas A-M. Imbalance between fibrin clot formation and fibrinolysis predicts cardiovascular events in patients with stable coronary artery disease. Thromb Haemost 2020; 120 (01) 75-82
• 13 Schmidt M, Maeng M, Madsen M, Sørensen HT, Jensen LO, Jakobsen C-J. The Western Denmark Heart Registry: its influence on cardiovascular patient care. J Am Coll Cardiol 2018; 71 (11) 1259-1272
• 14 Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas A-M, Kristensen SD. Determinants of reduced antiplatelet effect of aspirin in patients with stable coronary artery disease. PLoS One 2015; 10 (05) e0126767
• 15 McPherson R. Genome-wide association studies of cardiovascular disease in European and non-European populations. Curr Genet Med Rep 2014; 2 (01) 1-12
• 16 Christiansen MK, Nyegaard M, Pedersen LN. , et al. A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering. Atherosclerosis 2017; 257: 172-178
• 17 Ripatti S, Tikkanen E, Orho-Melander M. , et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 2010; 376 (9750): 1393-1400
• 18 Carter AM, Cymbalista CM, Spector TD, Grant PJ. EuroCLOT Investigators. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2783-2789
• 19 Chow CK, Pell ACH, Walker A, O'Dowd C, Dominiczak AF, Pell JP. Families of patients with premature coronary heart disease: an obvious but neglected target for primary prevention. BMJ 2007; 335 (7618): 481-485
• 20 van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res 2018; 122 (03) 433-443
• 21 Hosoi E. Biological and clinical aspects of ABO blood group system. J Med Invest 2008; 55 (3-4): 174-182
• 22 Vasan SK, Rostgaard K, Majeed A. , et al. ABO blood group and risk of thromboembolic and arterial disease: a study of 1.5 million blood donors. Circulation 2016; 133 (15) 1449-1457
• 23 Dentali F, Sironi AP, Ageno W. , et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature. Semin Thromb Hemost 2012; 38 (05) 535-548
• 24 Davies JA, Collins PW, Hathaway LS, Bowen DJ. von Willebrand factor: evidence for variable clearance in vivo according to Y/C1584 phenotype and ABO blood group. J Thromb Haemost 2008; 6 (01) 97-103
• 25 The broad institute. No Title. GTEx. Available at: www.gtexportal.org . Accessed June 7, 2020
• 26 Paterson AD, Lopes-Virella MF, Waggott D. , et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin. Arterioscler Thromb Vasc Biol 2009; 29 (11) 1958-1967
• 27 Shin S-Y, Fauman EB, Petersen A-K. , et al; Multiple Tissue Human Expression Resource (MuTHER) Consortium. An atlas of genetic influences on human blood metabolites. Nat Genet 2014; 46 (06) 543-550
• 28 GWAS ATLAS. Available at: https://atlas.ctglab.nl/PheWAS . Accessed June 7, 2020
• 29 Watanabe K, Stringer S, Frei O. , et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat Genet 2019; 51 (09) 1339-1348
• 30 Marchi R, Rojas H. Effect of von Willebrand factor on clot structure and lysis. Blood Coagul Fibrinolysis 2015; 26 (05) 533-536
• 31 Bochenek M, Zalewski J, Sadowski J, Undas A. Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease. J Thromb Thrombolysis 2013; 35 (02) 264-270
• 32 Sambola A, García Del Blanco B, Ruiz-Meana M. , et al. Increased von Willebrand factor, P-selectin and fibrin content in occlusive thrombus resistant to lytic therapy. Thromb Haemost 2016; 115 (06) 1129-1137
• 33 Pieters M, Guthold M, Nunes CM, de Lange Z. Interpretation and validation of maximum absorbance data obtained from turbidimetry analysis of plasma clots. Thromb Haemost 2020; 120 (01) 44-54
• 34 Mörtberg J, Blombäck M, Wallén Å, He S, Jacobson SH, Spaak J. Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease. Blood Coagul Fibrinolysis 2016; 27 (04) 401-407
• 35 Undas A, Nycz K, Pastuszczak M, Stompor T, Zmudka K. The effect of chronic kidney disease on fibrin clot properties in patients with acute coronary syndrome. Blood Coagul Fibrinolysis 2010; 21 (06) 522-527