Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.


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(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) 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(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) 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.

DOI: 10.1161/ATVBAHA.113.302088

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@article{Huang2014GenomewideAS, title={Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, author={Jie Huang and Jennifer E Huffman and Munekazu Yamakuchi and Stella Trompet and Folkert W. Asselbergs and Maria Sabater-Lleal and David-Alexandre Tr{\'e}gou{\"{e}t and Wei-Min Chen and Nicholas L. Smith and Marcus E. Kleber and So-Youn Shin and Diane M . Becker and Weihong Tang and Abbas Dehghan and Andrew D. Johnson and Vinh Truong and Lasse Folkersen and Qiong Yang and Tiphaine Oudot-Mellkah and Brendan M. Buckley and Jason H. Moore and Frances M. K. Williams and Harry Campbell and Guenther Silbernagel and Veronique Vitart and Igor Rudan and Geoffrey H. Tofler and Gerjan J. Navis and Anita L. DeStefano and Alan F. Wright and Ming-Huei Chen and Anton J M de Craen and Bradford Worrall and Alicja R. Rudnicka and Ann Rumley and Ebony B Bookman and Bruce M . Psaty and Fang Chen and Keith L. Keene and Oscar H. Franco and Bernhard B{\"{o}hm and Andr{\'e} G. Uitterlinden and Angela M. Carter and J Wouter Jukema and Naveed Sattar and Joshua C Bis and M. Arfan Ikram and Michele M Sale and Barbara Mcknight and Myriam Fornage and Ian Ford and Kent D. Taylor and Pieternella E Slagboom and Wendy L. Mcardle and Fang-Chi Hsu and Anders Franco-Cereceda and Alison H. Goodall and Lisa R Yanek and Karen L. Furie and M. Kelli Cushman and Albert Hofman and Jacqueline C. M. Witteman and Aaron R . Folsom and Saonli Basu and Nena Matijevic and Wiek H van Gilst and James F Wilson and Rudi G. J. Westendorp and Sekar Kathiresan and Muredach P. Reilly and Russell P Tracy and Ozren Pola{\vs}ek and Bernhard Rudolf Winkelmann and Peter J. Grant and Hans L. Hillege and François Cambien and David J M Stott and Gordon D . O . Lowe and Tim D. Spector and James B. Meigs and Winfried Marz and Per Eriksson and Lewis C . Becker and Pierre-Emmanuel Morange and Nicole Soranzo and Scott M. Williams and Caroline Hayward and Pim van der Harst and Anders Hamsten and Charles J. Lowenstein and David P. Strachan and Christopher J. O'Donnell}, journal={Arteriosclerosis, thrombosis, and vascular biology}, year={2014}, volume={34 5}, pages={1093-101} }