Identification of Potential Biological Factors Affecting the Treatment of Ticagrelor After Percutaneous Coronary Intervention in the Chinese Population

Dongdong Yuan, Xiangfen Shi, Liping Gao, Gaobiao Wan, Hanjuan Zhang, Yuling Yang, Yujie Zhao, Didi Sun, Dongdong Yuan, Xiangfen Shi, Liping Gao, Gaobiao Wan, Hanjuan Zhang, Yuling Yang, Yujie Zhao, Didi Sun

Abstract

Background: Generally, many individual factors can affect the clinical application of drugs, of which genetic factors contribute more than 20%. Ticagrelor is a new class of receptor inhibitors receptor antagonist of P2Y12 and is used as an antiplatelet agents. But it is not affected by the influence of CYP2C19 polymorphism. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of ticagrelor in the antiplatelet efficacy and safety, through pharmacogenomics research.

Methods: Whole-exome sequencing (WES) was performed in 100 patients after PCI with ticagrelor treatment. Clinical characteristics and WES of patients were used to performed genome-wide association analysis (GWAS), region-based tests of rare DNA variant to find the influencing factors of antiplatelet effect to ticagrelor and bleeding events. Co-expression, protein-protein interaction (PPI) network and pathway enrichment analysis were then used to find possible genetic mechanisms. Atlas of GWAS (https://atlas.ctglab.nl/) were used for external data validation.

Results: DNAH17, PGS1 and ABCA1 as the potential variant genes are associated with the expected antiplatelet effect to ticagrelor. The affected pathways may include the synthesis and metabolism of lipoprotein cholesterol and the catabolic process of pyrimidine-containing compound (GO:0072529). Age, sex and PLT were found may be potential factors for ticagrelor bleeding events.

Conclusion: We systematically identified new genetic variants and some risk factors for reduced efficacy of ticagrelor and highlighted related genes that may be involved in antiplatelet effects and bleeding event of ticagrelor. Our results enhance the understanding of the absorption and metabolic mechanisms that influence antiplatelet response to ticagrelor treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT03161002. First Posted: May 19, 2017. https://ichgcp.net/clinical-trials-registry/NCT03161002.

Keywords: bleeding; inhibition of platelet aggregation; percutaneous coronary intervention; pharmacogenetic; ticagrelor; whole-exome sequencing.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2022 Yuan et al.

Figures

Figure 1
Figure 1
Schematic diagram of the study design.
Figure 2
Figure 2
Platelet function testing. (A) Platelet function in patients prior- and post-treatment with aspirin and ticagrelor. (B) The distribution of prior PRU, post PRU and IPA in patients.
Figure 3
Figure 3
The relationship between clinical characteristics and IPA. (A) A linear relationship was fitted for all characteristics with IPA. (B) The distribution of IPA in different sex and smoking groups.
Figure 4
Figure 4
Whole-exome association study with IPA. (A) Manhattan plots showing ACS susceptibility loci discovered in the Chinese ACS WES dataset. Horizontal lines represent the genome-wide threshold (P = 1.2 × 10–5, green). The 4 sites that survived the genome-wide threshold with gene symbols marked in the plot. (B) Q-Q plot. (C) The distribution of IPA in different SNP variation types. 0/0 None, 0/1 heterozygous, 1/1 homozygous variant.
Figure 5
Figure 5
The effects of eQTLs and sQTLs on genes expression. (A) The effect of eQTLs rs972925 on expression of SOCS3 in liver and whole blood. (B) The effect of eQTLs rs60460416 on expression of SOCS3 in liver and whole blood. (C) The effect of sQTLs rs972925 (top) or rs60460416 (bottom) on intron-expression ratio in whole blood. (D) The location of SNPs and genes in genome.
Figure 6
Figure 6
Region-based tests of rare and common DNA variants. (A and B) Manhattan plots showing P values for association with genes using the SKAT-CommonRare (A) and SKAT-O (B). (C) The schematic diagram shows the location of the variant site in each gene.
Figure 7
Figure 7
Co-expression analysis. (A and B) Expression correlation analysis among ticagrelor associated genes in the blood (A) and liver tissues (B).
Figure 8
Figure 8
Related pathways of variants. (A) The top 10 significant enrichment of gene sets. (B) PPI network for four Go gene sets.
Figure 9
Figure 9
UK Biobank resource for external data validation. (A) rs60460416. (B) rs2289752. (C) rs972925.

References

    1. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50(19):1844–1851. doi:10.1016/j.jacc.2007.07.053
    1. Lars W, Becker Richard C, Andrzej B, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–1057.
    1. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without Aspirin in high-risk patients after PCI. N Engl J Med. 2019;381(21):2032–2042. doi:10.1056/NEJMoa1908419
    1. Hahn J-Y, Song YB, Oh J-H, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial. Lancet. 2018;391(10127):1274–1284. doi:10.1016/S0140-6736(18)30493-8
    1. Hahn J-Y, Song YB, Oh J-H, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA. 2019;321(24):2428–2437. doi:10.1001/jama.2019.8146
    1. Scott SA, Sangkuhl K, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317–323. doi:10.1038/clpt.2013.105
    1. Mega JL, Simon T, Collet J-P, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821–1830. doi:10.1001/jama.2010.1543
    1. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet. 2010;3:556–566. doi:10.1161/CIRCGENETICS.110.958561
    1. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749):1320–1328. doi:10.1016/S0140-6736(10)61274-3
    1. Claassens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019;381:1621–1631. doi:10.1056/NEJMoa1907096
    1. Martin J, Williams AK, Klein MD, et al. Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting. Genet Med. 2020;22(1):160–169. doi:10.1038/s41436-019-0611-1
    1. Dangas G, Baber U, Sharma S, et al. Ticagrelor with aspirin or alone after complex PCI: the TWILIGHT-COMPLEX analysis. J Am Coll Cardiol. 2020;75(19):2414–2424. doi:10.1016/j.jacc.2020.03.011
    1. Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet. 2019;394(10204):1169–1180. doi:10.1016/S0140-6736(19)31887-2
    1. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791–1800. doi:10.1056/NEJMoa1500857
    1. Tousoulis D, Paroutoglou IP, Papageorgiou N, Charakida M, Stefanadis C. Recent therapeutic approaches to platelet activation in coronary artery disease. Pharmacol Ther. 2010;127(2):108–120. doi:10.1016/j.pharmthera.2010.05.001
    1. Zhu Q, Zhong W, Wang X, et al. Pharmacokinetic and pharmacogenetic factors contributing to platelet function recovery after single dose of ticagrelor in healthy subjects. Front Pharmacol. 2019;10:209. doi:10.3389/fphar.2019.00209
    1. Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of Chinese Journal of Cardiology. 2019 Chinese Society of Cardiology (CSC) guidelines for the diagnosis and management of patients with ST-segment elevation myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi. 2019;47(10):766–783. doi:10.3760/cma.j.issn.0253-3758.2019.10.003
    1. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–2747. doi:10.1161/CIRCULATIONAHA.110.009449
    1. Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12(16):1521–1537. doi:10.1016/j.jcin.2019.03.034
    1. Chang CC, Chow CC, Tellier LC, et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4(1):7. doi:10.1186/s13742-015-0047-8
    1. Ardlie KG, Deluca DS, Segrè AV. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648–660. doi:10.1126/science.1262110
    1. Lee S, Emond MJ, Bamshad MJ, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012;91(2):224–237. doi:10.1016/j.ajhg.2012.06.007
    1. Ionita-Laza I, Lee S, Makarov V, Buxbaum JD, Lin X. Sequence kernel association tests for the combined effect of rare and common variants. Am J Hum Genet. 2013;92(6):841–853. doi:10.1016/j.ajhg.2013.04.015
    1. Lamparter D, Marbach D, Rueedi R, Kutalik Z, Bergmann S. Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics. PLoS Comput Biol. 2016;12(1):e1004714. doi:10.1371/journal.pcbi.1004714
    1. Akiyama M, Ishigaki K, Sakaue S, et al. Characterizing rare and low-frequency height-associated variants in the Japanese population. Nat Commun. 2019;10(1):4393. doi:10.1038/s41467-019-12276-5
    1. Varenhorst C, Eriksson N, Å J, et al. Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J. 2015;36(29):1901–1912. doi:10.1093/eurheartj/ehv116
    1. Nardin M, Verdoia M, Pergolini P, et al. Impact of adenosine A2a receptor polymorphism rs5751876 on platelet reactivity in ticagrelor treated patients. Pharmacol Res. 2018;129:27–33. doi:10.1016/j.phrs.2017.12.035
    1. Zhong W-P, Wu H, Chen J-Y, et al. Genomewide association study identifies novel genetic loci that modify antiplatelet effects and pharmacokinetics of clopidogrel. Clin Pharmacol Ther. 2017;101(6):791–802. doi:10.1002/cpt.589
    1. Li M, Hu Y, Li H, et al. No effect of SLCO1B1 and CYP3A4/5 polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male subjects. Biol Pharm Bull. 2017;40(1):88–96. doi:10.1248/bpb.b16-00686
    1. Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297–1309. doi:10.1056/NEJMoa1205512
    1. Cuisset T, Verheugt FWA, Mauri L. Update on antithrombotic therapy after percutaneous coronary revascularisation. Lancet. 2017;390(10096):810–820. doi:10.1016/S0140-6736(17)31936-0
    1. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382(9892):614–623. doi:10.1016/S0140-6736(13)61170-8
    1. Montalescot G, Rangé G, Silvain J, et al. High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the Arctic study. Circulation. 2014;129(21):2136–2143. doi:10.1161/CIRCULATIONAHA.113.007524
    1. Stratz C, Bömicke T, Younas I, et al. Comparison of immature platelet count to established predictors of platelet reactivity during thienopyridine therapy. J Am Coll Cardiol. 2016;68(3):286–293. doi:10.1016/j.jacc.2016.04.056
    1. Verdoia M, Pergolini P, Rolla R, et al. Impact of long-term dual antiplatelet therapy on immature platelet count and platelet reactivity. Angiology. 2018;69(6):490–496. doi:10.1177/0003319717736407
    1. Chang SC, Heacock PN, Clancey CJ, Dowhan W. The PEL1 gene (renamed PGS1) encodes the phosphatidylglycero-phosphate synthase of Saccharomyces cerevisiae. J Biol Chem. 1998;273(16):9829–9836. doi:10.1074/jbc.273.16.9829
    1. Serricchio M, Vissa A, Kim PK, Yip CM, McQuibban GA. Cardiolipin synthesizing enzymes form a complex that interacts with cardiolipin-dependent membrane organizing proteins. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(4):447–457. doi:10.1016/j.bbalip.2018.01.007
    1. Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency genetic variants in common disease. Genome Biol. 2017;18(1):77. doi:10.1186/s13059-017-1212-4
    1. Santos AJM, Nogueira C, Ortega-Bellido M, Malhotra V. TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum. J Cell Biol. 2016;213(3):343–354. doi:10.1083/jcb.201603072
    1. Phillips MC. Is ABCA1 a lipid transfer protein? J Lipid Res. 2018;59(5):749–763. doi:10.1194/jlr.R082313

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