Integrin ß1 polymorphisms and bleeding risk after coronary artery stenting
- 47 Downloads
Bleeding complications following percutaneous coronary intervention associate with increased mortality. However, the underlying molecular mechanisms are insufficiently understood. Platelet recruitment and activation at sites of vascular injury depends on the function of integrin adhesion receptors. Besides GPIIbIIIa as the most abundant integrin receptor, platelets relevantly express ß1 integrins. Experimental evidence from in vivo studies suggests a significant role of ß1 integrins in primary haemostasis. However, little is known about the clinical impact of genetic alterations of the β1 subunit, which might contribute to bleeding complications in patients. In this study, we performed DNA sequencing of patients suffering from bleeding complications after coronary artery stenting according to TIMI or BARC classification. We isolated DNA samples from 741 patients out of a cohort from 14,160 patients recruited in seven randomized clinical trials between June 2000 and May 2011. Subsequently, Sanger sequencing was performed covering the β1 integrin cytoplasmic activation domain (exon16) and its non-coding upstream region. Out of 764 patients suffering from bleeding complications, 741 DNA samples were successfully sequenced. Genotype variation was detected for SNP rs2153875 located within the non-coding upstream region with following allele frequency in study population: CC (7.3%), CA (35%) and AA (57.8%), which is similar to a general population cohort. Further, genotype variation in SNP rs2153875 do not associate with the frequency of TIMI or BARC classified access or non-access site bleedings. Genotype variations of the β1 integrin activation domain do not associate with bleeding risk after PCI.
KeywordsIntegrins α2ß1 Polymorphism SNP rs2153875 Bleeding risk PCI
Coronary artery disease
Dual anti-platelet therapy
Intracoronary stenting and antithrombotic research regime
Polymerase chain reaction
Percutaneous coronary intervention
Randomized clinical trials
Single nucleotide polymorphism
The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
This work was supported by LMU Munich’s Institutional Strategy LMU excellent within the framework of the German Excellence Initiative (TP), by the DZHK (German Center for Cardiovascular Research) to SM [Clinical Platelet Therapy Research, 81Z1600214], the LMU Munich’s Medical Faculty Förderprogramm für Forschung und Lehre (FöFoLe) (EL) and by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 16-2014 to A.P.; No. 46-2016 to L.D).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Mehran R, Pocock S, Nikolsky E, Dangas GD, Clayton T, Claessen BE, Caixeta A, Feit F, Manoukian SV, White H, Bertrand M, Ohman EM, Parise H, Lansky AJ, Lincoff AM, Stone GW (2001) Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. JACC Cardiovasc Interven 4(6):654–664CrossRefGoogle Scholar
- 8.Kastrati A, Mehilli J, Schühlen H, Dirschinger J, Dotzer F, ten Berg JM, Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schömig A (2004) A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 350(3):232–238CrossRefGoogle Scholar
- 9.Mehilli J, Kastrati A, Schühlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schömig A (2004) Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 110(24):3627–3635CrossRefGoogle Scholar
- 10.Hausleiter J, Kastrati A, Mehilli J, Schühlen H, Pache J, Dotzer F, Glatthor C, Siebert S, Dirschinger J, Schömig A (2004) A randomized trial comparing phosphorylcholine-coated stenting with balloon angioplasty as well as abciximab with placebo for restenosis reduction in small coronary arteries. J Intern Med 256(5):388–397CrossRefGoogle Scholar
- 11.Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schühlen H, Dirschinger J, Berger PB, Schömig A (2006) Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 295(13):1531–1538CrossRefGoogle Scholar
- 12.Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Büttner HJ, Khattab AA, Schulz S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA, Dirschinger J, Richardt G, Berger PB, Schömig A (2008) Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 359(7):688–696CrossRefGoogle Scholar
- 13.Schulz S, Mehilli J, Neumann FJ, Schuster T, Massberg S, Valina C, Seyfarth M, Pache J, Laugwitz KL, Büttner HJ, Ndrepepa G, Schömig A, Kastrati A (2010) ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention. Eur Heart J 31(20):2482–2491CrossRefGoogle Scholar
- 14.Kastrati A, Neumann FJ, Schulz S, Massberg S, Byrne RA, Ferenc M, Laugwitz KL, Pache J, Ott I, Hausleiter J, Seyfarth M, Gick M, Antoniucci D, Schömig A, Berger PB, Mehilli J (2011) Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 365(21):1980–1989CrossRefGoogle Scholar
- 22.Sionova M, Blasko P, Jirous S, Vindis D, Rokyta R, Motovska Z (2017) Association of polymorphisms of platelet receptors GPIa (807C > T), GPVI (13254T > C), and P2Y12 (34C > T and H1/H2 haplotype) with increased risk of periprocedural bleeding in patients undergoing coronary angiography/percutaneous coronary intervention. Adv Interv Cardiol 3(49):202–209Google Scholar
- 25.Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P, Siegbahn A, Syvanen AC, Wadelius C, Wadelius M, Zimdahl-Gelling H, Yusuf S, Wallentin L (2013) Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127(13):1404–1412CrossRefGoogle Scholar