New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

Liu, X.; Xu, H.; Geng, Q.; Mak, W.-H.; Ling, F.; Su, Z.; Yang, F.; Zhang, T.; Chen, J.; Yang, H.; Wang, J.; Zhang, X.; Xu, X.; Jia, H.; Zhang, Z.; Zhong, S.

doi:10.1101/411165

bioRxiv · 10.1101/411165

New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

Liu, X.·Xu, H.·Geng, Q.·Mak, W.-H.·Ling, F.·Su, Z.·Yang, F.·Zhang, T.·Chen, J.·Yang, H.·Wang, J.·Zhang, X.·Xu, X.·Jia, H.·Zhang, Z.·Zhong, S.

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Abstract

ImportanceAlthough a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE by large-scale sequencing data.\n\nObjectiveTo identify the genetic variants that caused MACE.\n\nDesignAll patients in this study were allocated to dual antiplatelet therapy for up to 12 months and have the follow-up duration of 18 months.\n\nSettingA two-stage association study was performed.\n\nParticipantsWe evaluated the associations of genetic variants and MACE in 1961 patients with ACS undergoing PCI (2009-2012), including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort.\n\nMain Outcomes and MeasureThe primary clinical efficacy endpoint was the major adverse cardiovascular events (MACE) composite endpoint, including cardiovascular death, myocardial infarction (MI), stroke (CT or MR scan confirmed) and repeated revascularization (RR).\n\nResultsWe discovered and confirmed six new genotypes associated with MACE in patients with ACS. Of which, rs17064642 at MYOM2 increased the risk of MACE (hazard ratio [HR] 2.76; P = 2.95 x 10-9) and reached genome-wide significance. The other five suggestive variants were KRTAP10-4 (rs201441480), WDR24 (rs11640115), ECHS1 (rs140410716), AGAP3 (rs75750968) and NECAB1 (rs74569896). Notably, the expressions of MYOM2 and ECHS1 are down-regulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting MACE and achieved high predictive accuracy (0.809).\n\nConclusions and RelevanceWe identified six new genotypes associated with MACE and developed a superior classifier for predicting MACE. Our findings shed light on the pathogenesis of cardiovascular outcomes and may help clinician to make decision on the therapeutic intervention for ACS patients.\n\nTrial RegistrationThis study has been registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn, Registration number: ChiCTR-OCH-11001198).

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Liu, X., Xu, H., Geng, Q., Mak, W.-H., Ling, F., Su, Z., Yang, F., Zhang, T., Chen, J., Yang, H., Wang, J., Zhang, X., Xu, X., Jia, H., Zhang, Z., Zhong, S.. 2018-09-07. New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin. https://doi.org/10.1101/411165

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