TY - JOUR
T1 - Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
AU - Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group
AU - Huang, Jie
AU - Huffman, Jennifer E
AU - Yamkauchi, Munekazu
AU - Trompet, Stella
AU - Asselbergs, Folkert W
AU - Sabater-Lleal, Maria
AU - Trégouët, David-Alexandre
AU - Chen, Wei-Min
AU - Smith, Nicholas L
AU - Kleber, Marcus E
AU - Shin, So-Youn
AU - Becker, Diane M
AU - Tang, Weihong
AU - Dehghan, Abbas
AU - Johnson, Andrew D
AU - Truong, Vinh
AU - Folkersen, Lasse
AU - Yang, Qiong
AU - Oudot-Mellkah, Tiphaine
AU - Buckley, Brendan M
AU - Moore, Jason H
AU - Williams, Frances M K
AU - Campbell, Harry
AU - Silbernagel, Günther
AU - Vitart, Veronique
AU - Rudan, Igor
AU - Tofler, Geoffrey H
AU - Navis, Gerjan J
AU - Destefano, Anita
AU - Wright, Alan F
AU - Chen, Ming-Huei
AU - de Craen, Anton J M
AU - Worrall, Bradford B
AU - Rudnicka, Alicja R
AU - Rumley, Ann
AU - Bookman, Ebony B
AU - Psaty, Bruce M
AU - Chen, Fang
AU - Keene, Keith L
AU - Franco, Oscar H
AU - Böhm, Bernhard O
AU - Uitterlinden, Andre G
AU - Carter, Angela M
AU - Jukema, J Wouter
AU - Sattar, Naveed
AU - Bis, Joshua C
AU - Ikram, Mohammad A
AU - Wilson, James F
AU - Polasek, Ozren
AU - Hayward, Caroline
PY - 2014/2/27
Y1 - 2014/2/27
N2 - 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.
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.
U2 - 10.1161/ATVBAHA.113.302088
DO - 10.1161/ATVBAHA.113.302088
M3 - Article
C2 - 24578379
SN - 1079-5642
VL - 34
SP - 1093
EP - 1101
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -