TY - JOUR T1 - Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Yamakuchi, Munekazu A1 - Yamkauchi, Munekazu A1 - Trompet, Stella A1 - Asselbergs, Folkert W A1 - Sabater-Lleal, Maria A1 - Trégouët, David-Alexandre A1 - Chen, Wei-Min A1 - Smith, Nicholas L A1 - Kleber, Marcus E A1 - Shin, So-Youn A1 - Becker, Diane M A1 - Tang, Weihong A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Truong, Vinh A1 - Folkersen, Lasse A1 - Yang, Qiong A1 - Oudot-Mellkah, Tiphaine A1 - Buckley, Brendan M A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Campbell, Harry A1 - Silbernagel, Günther A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Tofler, Geoffrey H A1 - Navis, Gerjan J A1 - DeStefano, Anita A1 - Wright, Alan F A1 - Chen, Ming-Huei A1 - de Craen, Anton J M A1 - Worrall, Bradford B A1 - Rudnicka, Alicja R A1 - Rumley, Ann A1 - Bookman, Ebony B A1 - Psaty, Bruce M A1 - Chen, Fang A1 - Keene, Keith L A1 - Franco, Oscar H A1 - Böhm, Bernhard O A1 - Uitterlinden, André G A1 - Carter, Angela M A1 - Jukema, J Wouter A1 - Sattar, Naveed A1 - Bis, Joshua C A1 - Ikram, Mohammad A A1 - Sale, Michèle M A1 - McKnight, Barbara A1 - Fornage, Myriam A1 - Ford, Ian A1 - Taylor, Kent A1 - Slagboom, P Eline A1 - McArdle, Wendy L A1 - Hsu, Fang-Chi A1 - Franco-Cereceda, Anders A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Furie, Karen L A1 - Cushman, Mary A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Wilson, James F A1 - Westendorp, Rudi G J A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Tracy, Russell P A1 - Polasek, Ozren A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Cambien, Francois A1 - Stott, David J A1 - Lowe, Gordon D A1 - Spector, Timothy D A1 - Meigs, James B A1 - März, Winfried A1 - Eriksson, Per A1 - Becker, Lewis C A1 - Morange, Pierre-Emmanuel A1 - Soranzo, Nicole A1 - Williams, Scott M A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Lowenstein, Charles J A1 - Strachan, David P A1 - O'Donnell, Christopher J KW - Aged KW - Cells, Cultured KW - Coronary Artery Disease KW - Endothelial Cells KW - Europe KW - Female KW - Gene Expression Regulation KW - Gene Silencing KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - R-SNARE Proteins KW - Risk Factors KW - Stroke KW - Syntaxin 1 KW - Tissue Plasminogen Activator KW - Transfection KW - United States KW - Up-Regulation AB -

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.

VL - 34 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract ER -