Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Jie Huang, Jennifer E. Huffman, Munekazu Yamkauchi, Stella Trompet, Folkert W. Asselbergs, Maria Sabater-Lleal, David-Alexandre Tregouet, Wei-Min Chen, Nicholas L. Smith, Marcus E. Kleber, So-Youn Shin, Diane M. Becker, Weihong Tang, Abbas Dehghan, Andrew D. Johnson, [No Value] Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M. BuckleyJason H. Moore, Frances M. K. Williams, Harry Campbell, Guenther Silbernagel, Veronique Vitart, Igor Rudan, Geoffrey H. Tofler, Gerjan J. Navis, Anita DeStefano, Alan F. Wright, Ming-Huei Chen, Anton J. M. de Craen, Bradford B. Worrall, Alicja R. Rudnicka, Ann Rumley, Ebony B. Bookman, Bruce M. Psaty, Fang Chen, Keith L. Keene, Oscar H. Franco, Bernhard O. Boehm, Andre G. Uitterlinden, Angela M. Carter, J. Wouter Jukema, Naveed Sattar, Joshua C. Bis, Mohammad A. Ikram, Wiek H. van Gilst, Hans L. Hillege, Pim van der Harst, CHARGE Consortium Hemostatic

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

Objective Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

Approach and Results Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P

Conclusions We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

Original languageEnglish
Pages (from-to)1093-1101
Number of pages9
JournalArteriosclerosis thrombosis and vascular biology
Volume34
Issue number5
DOIs
Publication statusPublished - May-2014

Keywords

  • fibrinolysis
  • genome-wide association study
  • hemostasis
  • meta-analysis
  • tissue plasminogen activator
  • VON-WILLEBRAND-FACTOR
  • CORONARY-ARTERY-DISEASE
  • ACUTE ISCHEMIC-STROKE
  • MYOCARDIAL-INFARCTION
  • PLASMA-LEVELS
  • GENETIC-VARIATION
  • RISK
  • HEART
  • POLYMORPHISMS
  • INHIBITOR-1

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