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

Abstract

Dongdong Yuan,1 Xiangfen Shi,2 Liping Gao,1 Gaobiao Wan,1 Hanjuan Zhang,1 Yuling Yang,1 Yujie Zhao,1 Didi Sun1 1Department of Medicine, The 7th People’s Hospital of Zhengzhou, Zhengzhou, 450000, Henan, People’s Republic of China; 2The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People’s Republic of ChinaCorrespondence: Didi Sun, Email [email protected]: 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://clinicaltrials.gov/ct2/show/study/NCT03161002.Keywords: ticagrelor, percutaneous coronary intervention, bleeding, inhibition of platelet aggregation, pharmacogenetic, whole-exome sequencing

Keywords

• ticagrelor
• percutaneous coronary intervention
• bleeding
• inhibition of platelet aggregation
• pharmacogenetic
• whole-exome sequencing