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 Trégouët; Wei Min Chen; Nicholas L. Smith; Marcus E. Kleber; So Youn Shin; Diane M. Becker; Weihong Tang; Abbas Dehghan; Andrew D. Johnson; Vinh Truong; Lasse Folkersen; Qiong Yang; Tiphaine Oudot-Mellkah; Brendan M. Buckley; Jason H. Moore; Frances M.K. Williams; Harry Campbell; Günther 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. Böhm; Andre G. Uitterlinden; Angela M. Carter; J. Wouter Jukema; Naveed Sattar; Joshua C. Bis; Mohammad A. Ikram; Michèle M. Sale; Barbara McKnight; Myriam Fornage; Ian Ford; Kent Taylor; P. Eline Slagboom; Wendy L. McArdle; Fang Chi Hsu; Anders Franco-Cereceda; Alison H. Goodall; Lisa R. Yanek; Karen L. Furie; Mary Cushman; Albert Hofman; Jacqueline C.M. Witteman; Aaron R. Folsom; Saonli Basu; Nena Matijevic; Wiek H. Van Gilst; James F. Wilson; Rudi G.J. Westendorp; Sekar Kathiresan; Muredach P. Reilly; Russell P. Tracy; Ozren Polasek; Bernhard R. Winkelmann; Peter J. Grant; Hans L. Hillege; Francois Cambien; David J. Stott; Gordon D. Lowe; Timothy D. Spector; James B. Meigs; Winfried Marz; Per Eriksson; Lewis C. Becker; Pierre Emmanuel Morange; Nicole Soranzo; Scott M. Williams; Caroline Hayward; Pim Van Der Harst; Anders Hamsten; Charles J. Lowenstein; David P. Strachan; Christopher J. O'Donnell

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 Trégouët, Wei Min Chen, Nicholas L. Smith, Marcus E. Kleber, So Youn Shin, Diane M. Becker, Weihong Tang, Abbas Dehghan, Andrew D. Johnson, Vinh Truong, Lasse Folkersen, Qiong Yang, Tiphaine Oudot-Mellkah, Brendan M. BuckleyJason H. Moore, Frances M.K. Williams, Harry Campbell, Günther 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. Böhm, Andre G. Uitterlinden, Angela M. Carter, J. Wouter Jukema, Naveed Sattar, Joshua C. Bis, Mohammad A. Ikram, Michèle M. Sale, Barbara McKnight, Myriam Fornage, Ian Ford, Kent Taylor, P. Eline Slagboom, Wendy L. McArdle, Fang Chi Hsu, Anders Franco-Cereceda, Alison H. Goodall, Lisa R. Yanek, Karen L. Furie, Mary Cushman, Albert Hofman, Jacqueline C.M. Witteman, Aaron R. Folsom, Saonli Basu, Nena Matijevic, Wiek H. Van Gilst, James F. Wilson, Rudi G.J. Westendorp, Sekar Kathiresan, Muredach P. Reilly, Russell P. Tracy, Ozren Polasek, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Francois Cambien, David J. Stott, Gordon D. Lowe, Timothy D. Spector, James B. Meigs, Winfried Marz, Per Eriksson, Lewis C. Becker, Pierre Emmanuel Morange, Nicole Soranzo, Scott M. Williams, Caroline Hayward, Pim Van Der Harst, Anders Hamsten, Charles J. Lowenstein, David P. Strachan, Christopher J. O'Donnell

School of Medicine

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

24 Scopus citations

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<5.0×10). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10) 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=0.50) within exon 5 of PLAT (P=2.0×10). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10) 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.

Original language	English (US)
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
State	Published - May 2014

Keywords

fibrinolysis
genome-wide association study
hemostasis
meta-analysis
tissue plasminogen activator

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/ATVBAHA.113.302088

Cite this

Huang, J., Huffman, J. E., Yamkauchi, M., Trompet, S., Asselbergs, F. W., Sabater-Lleal, M., Trégouët, D. A., Chen, W. M., Smith, N. L., Kleber, M. E., Shin, S. Y., Becker, D. M., Tang, W., Dehghan, A., Johnson, A. D., Truong, V., Folkersen, L., Yang, Q., Oudot-Mellkah, T., ... O'Donnell, C. J. (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

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

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

Huang, J, Huffman, JE, Yamkauchi, M, Trompet, S, Asselbergs, FW, Sabater-Lleal, M, Trégouët, DA, Chen, WM, Smith, NL, Kleber, ME, Shin, SY, 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, MH, 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, Jukema, JW, Sattar, N, Bis, JC, Ikram, MA, Sale, MM, McKnight, B, Fornage, M, Ford, I, Taylor, K, Slagboom, PE, McArdle, WL, Hsu, FC, 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, Marz, W, Eriksson, P, Becker, LC, Morange, PE, Soranzo, N, Williams, SM, Hayward, C, Van Der Harst, P, Hamsten, A, Lowenstein, CJ, Strachan, DP & O'Donnell, CJ 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

@article{9fb343ee87ee46a688439e44c5bf664c,

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 (P<5.0×10). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10) 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=0.50) within exon 5 of PLAT (P=2.0×10). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10) 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.",

keywords = "fibrinolysis, genome-wide association study, hemostasis, meta-analysis, tissue plasminogen activator",

author = "Jie Huang and Huffman, {Jennifer E.} and Munekazu Yamkauchi and Stella Trompet and Asselbergs, {Folkert W.} and Maria Sabater-Lleal and Tr{\'e}gou{\"e}t, {David Alexandre} and Chen, {Wei Min} and Smith, {Nicholas L.} and Kleber, {Marcus E.} and Shin, {So Youn} and Becker, {Diane M.} and Weihong Tang and Abbas Dehghan and Johnson, {Andrew D.} and Vinh Truong 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 G{\"u}nther Silbernagel and Veronique Vitart and Igor Rudan and Tofler, {Geoffrey H.} and Navis, {Gerjan J.} and Anita Destefano and Wright, {Alan F.} and Chen, {Ming Huei} 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 B{\"o}hm, {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 Sale, {Mich{\`e}le M.} and Barbara McKnight and Myriam Fornage and Ian Ford and Kent Taylor and Slagboom, {P. Eline} and McArdle, {Wendy L.} and Hsu, {Fang Chi} and Anders Franco-Cereceda and Goodall, {Alison H.} and Yanek, {Lisa R.} and Furie, {Karen L.} and Mary Cushman and Albert Hofman and Witteman, {Jacqueline C.M.} and Folsom, {Aaron R.} and Saonli Basu and Nena Matijevic and {Van Gilst}, {Wiek H.} and Wilson, {James F.} and Westendorp, {Rudi G.J.} and Sekar Kathiresan and Reilly, {Muredach P.} and Tracy, {Russell P.} and Ozren Polasek and Winkelmann, {Bernhard R.} and Grant, {Peter J.} and Hillege, {Hans L.} and Francois Cambien and Stott, {David J.} and Lowe, {Gordon D.} and Spector, {Timothy D.} and Meigs, {James B.} and Winfried Marz and Per Eriksson and Becker, {Lewis C.} and Morange, {Pierre Emmanuel} and Nicole Soranzo and Williams, {Scott M.} and Caroline Hayward and {Van Der Harst}, Pim and Anders Hamsten and Lowenstein, {Charles J.} and Strachan, {David P.} and O'Donnell, {Christopher J.}",

year = "2014",

month = may,

doi = "10.1161/ATVBAHA.113.302088",

language = "English (US)",

volume = "34",

pages = "1093--1101",

journal = "Arteriosclerosis, thrombosis, and vascular biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

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 - 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 - Sale, Michèle M.

AU - McKnight, Barbara

AU - Fornage, Myriam

AU - Ford, Ian

AU - Taylor, Kent

AU - Slagboom, P. Eline

AU - McArdle, Wendy L.

AU - Hsu, Fang Chi

AU - Franco-Cereceda, Anders

AU - Goodall, Alison H.

AU - Yanek, Lisa R.

AU - Furie, Karen L.

AU - Cushman, Mary

AU - Hofman, Albert

AU - Witteman, Jacqueline C.M.

AU - Folsom, Aaron R.

AU - Basu, Saonli

AU - Matijevic, Nena

AU - Van Gilst, Wiek H.

AU - Wilson, James F.

AU - Westendorp, Rudi G.J.

AU - Kathiresan, Sekar

AU - Reilly, Muredach P.

AU - Tracy, Russell P.

AU - Polasek, Ozren

AU - Winkelmann, Bernhard R.

AU - Grant, Peter J.

AU - Hillege, Hans L.

AU - Cambien, Francois

AU - Stott, David J.

AU - Lowe, Gordon D.

AU - Spector, Timothy D.

AU - Meigs, James B.

AU - Marz, Winfried

AU - Eriksson, Per

AU - Becker, Lewis C.

AU - Morange, Pierre Emmanuel

AU - Soranzo, Nicole

AU - Williams, Scott M.

AU - Hayward, Caroline

AU - Van Der Harst, Pim

AU - Hamsten, Anders

AU - Lowenstein, Charles J.

AU - Strachan, David P.

AU - O'Donnell, Christopher J.

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 (P<5.0×10). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10) 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=0.50) within exon 5 of PLAT (P=2.0×10). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10) 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). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10) 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=0.50) within exon 5 of PLAT (P=2.0×10). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10) 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.

KW - fibrinolysis

KW - genome-wide association study

KW - hemostasis

KW - meta-analysis

KW - tissue plasminogen activator

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U2 - 10.1161/ATVBAHA.113.302088

DO - 10.1161/ATVBAHA.113.302088

M3 - Article

C2 - 24578379

AN - SCOPUS:84899653256

SN - 1079-5642

VL - 34

SP - 1093

EP - 1101

JO - Arteriosclerosis, thrombosis, and vascular biology

JF - Arteriosclerosis, thrombosis, and vascular biology

IS - 5

ER -

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

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