Title | Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Huang J, Huffman JE, Yamakuchi M, Yamkauchi M, Trompet S, Asselbergs FW, Sabater-Lleal M, Tregouet 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 |
Secondary Authors | O'Donnell CJ |
Corporate Authors | Cohorts for Heart and Aging Research in Genome Epidemiology(CHARGE) Consortium Neurology Working Group, CARDIoGRAM Consortium, CHARGE Consortium Hemostatic Factor Working Group |
Journal | Arterioscler Thromb Vasc Biol |
Volume | 34 |
Issue | 5 |
Pagination | 1093-101 |
Date Published | 2014 May |
ISSN | 1524-4636 |
Keywords | Aged, 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 | 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 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 |
Alternate Journal | Arterioscler Thromb Vasc Biol |
PubMed ID | 24578379 |
PubMed Central ID | PMC4009733 |
Grant List | HHSN268201100010C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom U01 HG005157 / HG / NHGRI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States HHSN268201100012C / 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 / CSO_ / 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 HHSN268201100008C / HL / NHLBI NIH HHS / United States P01 HL065608 / HL / NHLBI NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States G0000934 / MRC_ / 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 NS17950 / NS / NINDS NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL093029 / HL / NHLBI NIH HHS / United States ZIA HL006002-07 / ImNIH / Intramural 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 LM010098 / LM / NLM NIH HHS / United States K24 DK080140 / DK / NIDDK NIH HHS / United States R01-HL093029 / HL / NHLBI NIH HHS / United States M01 RR000052 / RR / NCRR NIH HHS / United States R01 HL080295 / HL / NHLBI NIH HHS / United States U01 HL072518 / HL / NHLBI 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 / ImNIH / Intramural NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States / WT_ / Wellcome Trust / United Kingdom P30 AG010129 / AG / NIA 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 |