Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Jie Huang; Jennifer E. Huffman; Munekazu Yamkauchi; Stella Trompet; Folkert W. Asselbergs; Maria Sabater-Lleal; David-Alexandre Tregouet; Wei-Min Chen; Nicholas L. Smith; Marcus E. Kleber; So-Youn Shin; Diane M. Becker; Weihong Tang; Abbas Dehghan; Andrew D. Johnson; [No Value] Vinh Truong; Lasse Folkersen; Qiong Yang; Tiphaine Oudot-Mellkah; Brendan M. Buckley; Jason H. Moore; Frances M. K. Williams; Harry Campbell; Guenther Silbernagel; Veronique Vitart; Igor Rudan; Geoffrey H. Tofler; Gerjan J. Navis; Anita DeStefano; Alan F. Wright; Ming-Huei Chen; Anton J. M. de Craen; Bradford B. Worrall; Alicja R. Rudnicka; Ann Rumley; Ebony B. Bookman; Bruce M. Psaty; Fang Chen; Keith L. Keene; Oscar H. Franco; Bernhard O. Boehm; Andre G. Uitterlinden; Angela M. Carter; J. Wouter Jukema; Naveed Sattar; Joshua C. Bis; Mohammad A. Ikram; Wiek H. van Gilst; Hans L. Hillege; Pim van der Harst; CHARGE Consortium Hemostatic

doi:10.1161/ATVBAHA.113.302088

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Jie Huang, Jennifer E. Huffman, Munekazu Yamkauchi, Stella Trompet, Folkert W. Asselbergs, Maria Sabater-Lleal, David-Alexandre Tregouet, Wei-Min Chen, Nicholas L. Smith, Marcus E. Kleber, So-Youn Shin, Diane M. Becker, Weihong Tang, Abbas Dehghan, Andrew D. Johnson, [No Value] Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M. BuckleyJason H. Moore, Frances M. K. Williams, Harry Campbell, Guenther Silbernagel, Veronique Vitart, Igor Rudan, Geoffrey H. Tofler, Gerjan J. Navis, Anita DeStefano, Alan F. Wright, Ming-Huei Chen, Anton J. M. de Craen, Bradford B. Worrall, Alicja R. Rudnicka, Ann Rumley, Ebony B. Bookman, Bruce M. Psaty, Fang Chen, Keith L. Keene, Oscar H. Franco, Bernhard O. Boehm, Andre G. Uitterlinden, Angela M. Carter, J. Wouter Jukema, Naveed Sattar, Joshua C. Bis, Mohammad A. Ikram, Wiek H. van Gilst, Hans L. Hillege, Pim van der Harst, CHARGE Consortium Hemostatic

Research output: Contribution to journal › Article › Academic › peer-review

23 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1093-1101
Number of pages	9
Journal	Arteriosclerosis thrombosis and vascular biology
Volume	34
Issue number	5
DOIs	https://doi.org/10.1161/ATVBAHA.113.302088
Publication status	Published - May-2014

Keywords

fibrinolysis
genome-wide association study
hemostasis
meta-analysis
tissue plasminogen activator
VON-WILLEBRAND-FACTOR
CORONARY-ARTERY-DISEASE
ACUTE ISCHEMIC-STROKE
MYOCARDIAL-INFARCTION
PLASMA-LEVELS
GENETIC-VARIATION
RISK
HEART
POLYMORPHISMS
INHIBITOR-1

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Huang, J., Huffman, J. E., Yamkauchi, M., Trompet, S., Asselbergs, F. W., Sabater-Lleal, M., Tregouet, D-A., Chen, W-M., Smith, N. L., Kleber, M. E., Shin, S-Y., Becker, D. M., Tang, W., Dehghan, A., Johnson, A. D., Vinh Truong, N. V., Folkersen, L., Yang, Q., Oudot-Mellkah, T., ... CHARGE Consortium Hemostatic (2014). Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2. Arteriosclerosis thrombosis and vascular biology, 34(5), 1093-1101. https://doi.org/10.1161/ATVBAHA.113.302088

Huang, Jie ; Huffman, Jennifer E. ; Yamkauchi, Munekazu ; Trompet, Stella ; Asselbergs, Folkert W. ; Sabater-Lleal, Maria ; Tregouet, David-Alexandre ; Chen, Wei-Min ; Smith, Nicholas L. ; Kleber, Marcus E. ; Shin, So-Youn ; Becker, Diane M. ; Tang, Weihong ; Dehghan, Abbas ; Johnson, Andrew D. ; Vinh Truong, [No Value] ; Folkersen, Lasse ; Yang, Qiong ; Oudot-Mellkah, Tiphaine ; Buckley, Brendan M. ; Moore, Jason H. ; Williams, Frances M. K. ; Campbell, Harry ; Silbernagel, Guenther ; 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. ; Boehm, Bernhard O. ; Uitterlinden, Andre G. ; Carter, Angela M. ; Jukema, J. Wouter ; Sattar, Naveed ; Bis, Joshua C. ; Ikram, Mohammad A. ; van Gilst, Wiek H. ; Hillege, Hans L. ; van der Harst, Pim ; CHARGE Consortium Hemostatic. / Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2. In: Arteriosclerosis thrombosis and vascular biology. 2014 ; Vol. 34, No. 5. pp. 1093-1101.

@article{8731bae3e616483ba4c21db46693034f,

title = "Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2",

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 (PConclusions 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.",

keywords = "fibrinolysis, genome-wide association study, hemostasis, meta-analysis, tissue plasminogen activator, VON-WILLEBRAND-FACTOR, CORONARY-ARTERY-DISEASE, ACUTE ISCHEMIC-STROKE, MYOCARDIAL-INFARCTION, PLASMA-LEVELS, GENETIC-VARIATION, RISK, HEART, POLYMORPHISMS, INHIBITOR-1",

author = "Jie Huang and Huffman, {Jennifer E.} and Munekazu Yamkauchi and Stella Trompet and Asselbergs, {Folkert W.} and Maria Sabater-Lleal and David-Alexandre Tregouet and Wei-Min Chen and Smith, {Nicholas L.} and Kleber, {Marcus E.} and So-Youn Shin and Becker, {Diane M.} and Weihong Tang and Abbas Dehghan and Johnson, {Andrew D.} and {Vinh Truong}, {[No Value]} and Lasse Folkersen and Qiong Yang and Tiphaine Oudot-Mellkah and Buckley, {Brendan M.} and Moore, {Jason H.} and Williams, {Frances M. K.} and Harry Campbell and Guenther Silbernagel and Veronique Vitart and Igor Rudan and Tofler, {Geoffrey H.} and Navis, {Gerjan J.} and Anita DeStefano and Wright, {Alan F.} and Ming-Huei Chen and {de Craen}, {Anton J. M.} and Worrall, {Bradford B.} and Rudnicka, {Alicja R.} and Ann Rumley and Bookman, {Ebony B.} and Psaty, {Bruce M.} and Fang Chen and Keene, {Keith L.} and Franco, {Oscar H.} and Boehm, {Bernhard O.} and Uitterlinden, {Andre G.} and Carter, {Angela M.} and Jukema, {J. Wouter} and Naveed Sattar and Bis, {Joshua C.} and Ikram, {Mohammad A.} and {van Gilst}, {Wiek H.} and Hillege, {Hans L.} and {van der Harst}, Pim and {CHARGE Consortium Hemostatic}",

year = "2014",

month = may,

doi = "10.1161/ATVBAHA.113.302088",

language = "English",

volume = "34",

pages = "1093--1101",

journal = "Arteriosclerosis thrombosis and vascular biology",

issn = "1079-5642",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "5",

}

Huang, J, Huffman, JE, 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, Vinh Truong, NV, 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, Boehm, BO, Uitterlinden, AG, Carter, AM, Jukema, JW, Sattar, N, Bis, JC, Ikram, MA, van Gilst, WH , Hillege, HL , van der Harst, P & CHARGE Consortium Hemostatic 2014, 'Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2', Arteriosclerosis thrombosis and vascular biology, vol. 34, no. 5, pp. 1093-1101. https://doi.org/10.1161/ATVBAHA.113.302088

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2. / Huang, Jie; Huffman, Jennifer E.; Yamkauchi, Munekazu; Trompet, Stella; Asselbergs, Folkert W.; Sabater-Lleal, Maria; Tregouet, David-Alexandre; Chen, Wei-Min; Smith, Nicholas L.; Kleber, Marcus E.; Shin, So-Youn; Becker, Diane M.; Tang, Weihong; Dehghan, Abbas; Johnson, Andrew D.; Vinh Truong, [No Value]; Folkersen, Lasse; Yang, Qiong; Oudot-Mellkah, Tiphaine; Buckley, Brendan M.; Moore, Jason H.; Williams, Frances M. K.; Campbell, Harry; Silbernagel, Guenther; 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.; Boehm, Bernhard O.; Uitterlinden, Andre G.; Carter, Angela M.; Jukema, J. Wouter; Sattar, Naveed; Bis, Joshua C.; Ikram, Mohammad A.; van Gilst, Wiek H.; Hillege, Hans L.; van der Harst, Pim; CHARGE Consortium Hemostatic.

In: Arteriosclerosis thrombosis and vascular biology, Vol. 34, No. 5, 05.2014, p. 1093-1101.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

AU - Huang, Jie

AU - Huffman, Jennifer E.

AU - Yamkauchi, Munekazu

AU - Trompet, Stella

AU - Asselbergs, Folkert W.

AU - Sabater-Lleal, Maria

AU - Tregouet, 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 - Vinh Truong, [No Value]

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, Guenther

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 - Boehm, 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 - van Gilst, Wiek H.

AU - Hillege, Hans L.

AU - van der Harst, Pim

AU - CHARGE Consortium Hemostatic

PY - 2014/5

Y1 - 2014/5

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 (PConclusions 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 (PConclusions 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.

KW - fibrinolysis

KW - genome-wide association study

KW - hemostasis

KW - meta-analysis

KW - tissue plasminogen activator

KW - VON-WILLEBRAND-FACTOR

KW - CORONARY-ARTERY-DISEASE

KW - ACUTE ISCHEMIC-STROKE

KW - MYOCARDIAL-INFARCTION

KW - PLASMA-LEVELS

KW - GENETIC-VARIATION

KW - RISK

KW - HEART

KW - POLYMORPHISMS

KW - INHIBITOR-1

U2 - 10.1161/ATVBAHA.113.302088

DO - 10.1161/ATVBAHA.113.302088

M3 - Article

VL - 34

SP - 1093

EP - 1101

JO - Arteriosclerosis thrombosis and vascular biology

JF - Arteriosclerosis thrombosis and vascular biology

SN - 1079-5642

IS - 5

ER -