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Targeted deep sequencing of the PEAR1 locus for platelet aggregation in European and African American families

机译：欧洲和非洲裔美国家庭血小板聚集的珍珠座的深度测序

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摘要

Coronary artery disease (CAD) remains a major cause of mortality and morbidity worldwide. The aggregation of activated platelets on a ruptured atherosclerotic plaque is a critical step in most acute cardiovascular events like myocardial infarction. Platelet aggregation both at baseline and after aspirin is highly heritable. Genome-wide association studies (GWAS) have identified a common variant within the first intron of the platelet endothelial aggregation receptor1 (PEAR1), to be robustly associated with platelet aggregation. In this study, we used targeted deep sequencing to fine-map the prior GWAS peak and identify additional rare variants of PEAR1 that account for missing heritability in platelet aggregation within the GeneSTAR families. In this study, 1709 subjects (1043 European Americans, EA and 666 African Americans, AA) from families in the GeneSTAR study were included. In vitro platelet aggregation in response to collagen, ADP and epinephrine was measured at baseline and 14 days after aspirin therapy (81 mg/day). Targeted deep sequencing of PEAR1 in addition to 2kb of upstream and downstream of the gene was performed. Under an additive genetic model, the association of single variants of PEAR1 with platelet aggregation phenotypes were examined. Additionally, we examined the association between the burden of PEAR1 rare non-synonymous variants and platelet aggregation phenotypes. Of 532 variants identified through sequencing, the intron 1 variant, rs12041331, was significantly associated with all platelet aggregation phenotypes at baseline and after platelet inhibition with aspirin therapy. rs12566888, which is in linkage disequilibrium with rs12041331, was associated with platelet aggregation phenotypes but to a lesser extent. In the EA families, the burden of PEAR1 missense variants was associated with platelet aggregation after aspirin therapy when the platelets were stimulated with epinephrine (p = 0.0009) and collagen (p = 0.03). In AAs, the burden of PEAR1 missense variants was associated, to a lesser degree, with platelet aggregation in response to epinephrine (p = 0.02) and ADP (p = 0.04). Our study confirmed that the GWAS-identified variant, rs12041331, is the strongest variant associated with platelet aggregation both at baseline and after aspirin therapy in our GeneSTAR families in both races. We identified additional association of rare missense variants in PEAR1 with platelet aggregation following aspirin therapy. However, we observed a racial difference in the contribution of these rare variants to the platelet aggregation, most likely due to higher residual missing heritability of platelet aggregation after accounting for rs12041331 in the EAs compared to AAs.
机译：冠状动脉疾病（CAD）仍然是全世界死亡率和发病率的主要原因。活化血小板在破裂的动脉粥样硬化斑块上的聚集是大多数急性心血管事件如心肌梗死的关键步骤。在基线和阿司匹林后的血小板聚集是高度遗传的。基因组 - 宽协会研究（GWAs）已经鉴定了血小板内皮聚集受体1（PEAL1）的第一个内含子内的常用变体，以鲁棒地与血小板聚集有关。在这项研究中，我们使用靶向的深度测序来精细映射到先前的GWAS峰，并鉴定珍珠的额外罕见变体，该珍珠氏菌属在基因达家族内血小板聚集中遗漏的遗传性。在本研究中，包括GeateStar研究中的1709名科目（1043名欧洲美国人，EA和666名非洲裔美国人，AA）。体外血小板聚集响应胶原蛋白，ADP和肾上腺素在基线测量，Aspirin治疗后14天（81毫克/天）。除了在基因上游的2KB之外，珍珠的靶向深度测序是珍珠的。在一种添加剂遗传模型下，检查了珍珠菌的单个变体与血小板聚集表型的关联。此外，我们检查了珍珠稀有的非同义变体和血小板聚集表型负担之间的关联。通过测序确定的532个变体，Intron 1变体RS12041331与基线的所有血小板聚集表型和血小板抑制后与阿司匹林疗法明显相关。 RS12566888与RS12041331的联动不平衡，与血小板聚集表型相关，但程度较小。在EA家庭中，珍珠氏菌毒素治疗后珍珠氏菌的负担与血小板刺激后（P = 0.0009）和胶原蛋白（P = 0.03）。在AAS中，Pear1密码变异的负担与较小程度相关联，响应肾上腺素（P = 0.02）和ADP（P = 0.04）。我们的研究证实，GWAS鉴定的变体RS12041331是与基线和阿司匹林疗法在两场比赛中的基因素治疗后相关的最强的变异。在阿司匹林治疗后，我们确定了珍珠菌中珍珠氏菌变异的额外关联。然而，我们观察到这些罕见变体对血小板聚集的贡献的种族差异，很可能是由于在EAS中占AAS中的Rs12041331后血小板聚集的剩余遗传性较高。

著录项

  • 来源
    《Platelets》 |2019年第3期|共7页
  • 作者

    Keramati Ali R.; Yanek Lisa R.; Lyer Kruthika; Taub Margaret A.; Ruczinski Ingo; Becker Diane M.; Becker Lewis C.; Faraday Nauder; Mathias Rasika A.;

  • 作者单位

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Dept Biostat Bloomberg Sch Publ Hlth Baltimore MD 21224 USA;

    Johns Hopkins Univ Dept Biostat Bloomberg Sch Publ Hlth Baltimore MD 21224 USA;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

    Johns Hopkins Univ Sch Med Div Gen Internal Med GeneSTAR Res Program Dept Med Baltimore MD;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 基础医学;
  • 关键词

    Deep targeted sequencing; PEAR1; platelet aggregation;

    机译：深度靶向测序;珍珠;血小板聚集;

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