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 Trégouët, Wei Min Chen, Nicholas L. Smith, Marcus E. Kleber, So Youn Shin, Diane M. Becker, Weihong Tang, Abbas Dehghan, Andrew D. Johnson, Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M. BuckleyJason H. Moore, Frances M K Williams, Harry Campbell, Günther 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. Böhm, Andre G. Uitterlinden, Angela M. Carter, J. Wouter Jukema, Naveed Sattar, Joshua C. Bis, Mohammad A. Ikram, Michèle M. Sale, Barbara McKnight, Myriam Fornage, Ian Ford, Kent Taylor, P. Eline Slagboom, Wendy L. McArdle, Fang Chi Hsu, Anders Franco-Cereceda, Alison H. Goodall, Lisa R. Yanek, Karen L. Furie, Mary Cushman, Albert Hofman, Jacqueline C M Witteman, Aaron R. Folsom, Saonli Basu, Nena Matijevic, Wiek H. Van Gilst, James F. Wilson, Rudi G J Westendorp, Sekar Kathiresan, Muredach P. Reilly, Russell P. Tracy, Ozren Polasek, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Francois Cambien, David J. Stott, Gordon D. Lowe, Timothy D. Spector, James B. Meigs, Winfried Marz, Per Eriksson, Lewis C. Becker, Pierre Emmanuel Morange, Nicole Soranzo, Scott M. Williams, Caroline Hayward, Pim Van Der Harst, Anders Hamsten, Charles J. Lowenstein, David P. Strachan, Christopher J. O'Donnell

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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<5.0×10). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r=0.50) within exon 5 of PLAT (P=2.0×10). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke. 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 (US)
Pages (from-to)1093-1101
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • fibrinolysis
  • genome-wide association study
  • hemostasis
  • meta-analysis
  • tissue plasminogen activator

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