The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA.
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
J Thromb Haemost. 2021 Aug;19(8):2019-2028. doi: 10.1111/jth.15345. Epub 2021 May 30.
Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.
We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.
Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.
This work provides new evidence for a role of FGL1 in hemostasis.
利用常见的、罕见的变异体和功能丰富的变异体的靶向外显子组，已经发现了新的基因，这些基因有助于人群中风险因素的变化。纤溶酶原激活物抑制剂 1（PAI-1）、组织型纤溶酶原激活物（tPA）和血浆 D-二聚体是纤维蛋白溶解系统的重要组成部分。关于 PAI-1、tPA 和 D-二聚体，很少有大规模的全基因组或外显子组范围的研究。
我们试图通过外显子组方法发现新的遗传基因座，这些基因座有助于这些特征的变化。
对来自具有不同研究设计的 12 个欧洲血统队列的 PAI-1（n=15603）、tPA（n=6876）和 D-二聚体（n=19306）进行了队列水平分析和固定效应荟萃分析，包括单变量分析和基于基因的负担测试。
五个位于 NME7、FGL1 和纤维蛋白原基因座的变异体都与 D-二聚体水平相关，达到了全基因组显著性水平（P<5×10）。我们寻求对这 5 个变异体进行复制，以及在发现中对 45 个高度内插的变异体进行复制，这些变异体的 P<1×10。在一个独立的队列中，观察到这 5 个显著关联中的 3 个得到了复制，包括 FGL1（纤维蛋白原样 1）中的一个新的和不常见的（0.013 等位基因频率）编码变异 p.Trp256Leu，它增加了血浆 D-二聚体水平。此外，候选基因方法揭示了 SERPINB2 中一个编码变异体（rs143202684-C）的提示性关联，在复制分析中还存在与一致效应相关的提示性关联，包括与 D-二聚体水平升高相关的 SCARB1 内含子变异体（rs11057830-A）。
这项工作为 FGL1 在止血中的作用提供了新的证据。
