Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial
STXBP5
and
STX2
Authors: Huang Jie , Huffman Jennifer E. , Yamakuchi Munekazu , Trompet Stella , Asselbergs Folkert W. , Sabater-Lleal Maria , Trégouët David-Alexandre , Chen Wei-Min , Smith Nicholas L. , Kleber Marcus E. , Shin So-Youn , Becker Diane M. , Tang Weihong , Dehghan Abbas , Johnson Andrew D. , Truong Vinh , Folkersen Lasse , Yang Qiong , Oudot-Mellkah Tiphaine , Buckley Brendan M. , Moore Jason H. , Williams Frances M.K. , Campbell Harry , Silbernagel Günther , Vitart Veronique , Rudan Igor , Tofler Geoffrey H. , Navis Gerjan J. , DeStefano Anita , Wright Alan F. , Chen Ming-Huei , de Craen Anton J.M. , Worrall Bradford B. , Rudnicka Alicja R. , Rumley Ann , Bookman Ebony B. , Psaty Bruce M. , Chen Fang , Keene Keith L. , Franco Oscar H. , Böhm Bernhard O. , Uitterlinden Andre G. , Carter Angela M. , Jukema J. Wouter , Sattar Naveed , Bis Joshua C. , Ikram Mohammad A. , Sale Michèle M. , McKnight Barbara , Fornage Myriam , Ford Ian , Taylor Kent , Slagboom P. Eline , McArdle Wendy L. , Hsu Fang-Chi , Franco-Cereceda Anders , Goodall Alison H. , Yanek Lisa R. , Furie Karen L. , Cushman Mary , Hofman Albert , Witteman Jacqueline C.M. , Folsom Aaron R. , Basu Saonli , Matijevic Nena , van Gilst Wiek H. , Wilson James F. , Westendorp Rudi G.J. , Kathiresan Sekar , Reilly Muredach P. , Tracy Russell P. , Polasek Ozren , Winkelmann Bernhard R. , Grant Peter J. , Hillege Hans L. , Cambien Francois , Stott David J. , Lowe Gordon D. , Spector Timothy D. , Meigs James B. , Marz Winfried , Eriksson Per , Becker Lewis C. , Morange Pierre-Emmanuel , Soranzo Nicole , Williams Scott M. , Hayward Caroline , van der Harst Pim , Hamsten Anders , Lowenstein Charles J. , Strachan David P. , O’Donnell Christopher J. 
Published: February 2014

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.