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

Thursday,2014-05-29 14:48 America/Los_Angeles — poolea2
TitleGenome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
Publication TypeJournal Article
Year of Publication2014
AuthorsHuang, J, Huffman, JE, Yamakuchi, M, Yamkauchi, M, Trompet, S, Asselbergs, FW, Sabater-Lleal, M, Trégouët, D-A, Chen, W-M, Smith, NL, Kleber, ME, Shin, S-Y, Becker, DM, Tang, W, Dehghan, A, Johnson, AD, Truong, V, Folkersen, L, Yang, Q, Oudot-Mellkah, T, Buckley, BM, Moore, JH, Williams, FMK, Campbell, H, Silbernagel, G, Vitart, V, Rudan, I, Tofler, GH, Navis, GJ, DeStefano, A, Wright, AF, Chen, M-H, de Craen, AJM, Worrall, BB, Rudnicka, AR, Rumley, A, Bookman, EB, Psaty, BM, Chen, F, Keene, KL, Franco, OH, Böhm, BO, Uitterlinden, AG, Carter, AM, J Jukema, W, Sattar, N, Bis, JC, Ikram, MA, Sale, MM, McKnight, B, Fornage, M, Ford, I, Taylor, K, P Slagboom, E, McArdle, WL, Hsu, F-C, Franco-Cereceda, A, Goodall, AH, Yanek, LR, Furie, KL, Cushman, M, Hofman, A, Witteman, JCM, Folsom, AR, Basu, S, Matijevic, N, van Gilst, WH, Wilson, JF, Westendorp, RGJ, Kathiresan, S, Reilly, MP, Tracy, RP, Polasek, O, Winkelmann, BR, Grant, PJ, Hillege, HL, Cambien, F, Stott, DJ, Lowe, GD, Spector, TD, Meigs, JB, März, W, Eriksson, P, Becker, LC, Morange, P-E, Soranzo, N, Williams, SM, Hayward, C, van der Harst, P, Hamsten, A, Lowenstein, CJ, Strachan, DP, O'Donnell, CJ
Corporate/Institutional AuthorsCohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group, CARDIoGRAM consortium, CHARGE Consortium Hemostatic Factor Working Group
JournalArterioscler Thromb Vasc Biol
Volume34
Issue5
Pagination1093-101
Date Published2014 May
ISSN1524-4636
KeywordsAged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation
Abstract<p><b>OBJECTIVE: </b>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.</p><p><b>APPROACH AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>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.</p>
DOI10.1161/ATVBAHA.113.302088
Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID24578379
PubMed Central IDPMC4009733
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HL67466 / HL / NHLBI NIH HHS / United States
U01 HG005160 / HG / NHGRI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
HHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 HL065234 / HL / NHLBI NIH HHS / United States
UL1RR033176 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
HL65234 / HL / NHLBI NIH HHS / United States
P01 HL56091 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
P01 HL065608 / HL / NHLBI NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
U01 HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
R01 HL067466 / HL / NHLBI NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
R01 HL078635 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
P20 RR018787 / RR / NCRR NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL78635 / HL / NHLBI NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
P01 HL056091 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 NS34447 / NS / NINDS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
ZIA HL006002-07 / / Intramural NIH HHS / United States
NS17950 / NS / NINDS NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
P01 HL65608 / HL / NHLBI NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RR018787 / RR / NCRR NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R01 LM010098 / LM / NLM NIH HHS / United States
R01-HL093029 / HL / NHLBI NIH HHS / United States
M01 RR000052 / RR / NCRR NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
MC_PC_U127561128 / / Medical Research Council / United Kingdom
R01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HL072518 / HL / NHLBI NIH HHS / United States
U01 HG005157 / HG / NHGRI NIH HHS / United States
R01 HL059684 / HL / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
R01 NS034447 / NS / NINDS NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
R01 HL074061 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
Z99 HL999999 / / Intramural NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
1U01 HL072518 / HL / NHLBI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
M01 RR00052 / RR / NCRR NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
LM010098 / LM / NLM NIH HHS / United States

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