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

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... Full description

Journal Title: Arteriosclerosis Thrombosis, and Vascular Biology, 2014, Vol.34(5), pp.1093-1101
Main Author: Huang, E., Jie
Other Authors: Huffman, W., Jennifer , Yamkauchi, L., Munekazu , Trompet, E., Stella , Asselbergs, M., Folkert , Sabater-Lleal, D., Maria , Trégouët, M., David-Alexandre , Chen, H., Wei-Min , Smith, M.K., Nicholas , Kleber, H., Marcus , Shin, J., So-Youn , Becker, F., Diane , Tang, J.M., Weihong , Dehghan, B., Abbas , Johnson, R., Andrew , Truong, B., Vinh , Folkersen, M., Lasse , Yang, L., Qiong , Oudot-Mellkah, H., Tiphaine , Buckley, O., Brendan , Moore, G., Jason , Williams, M., Frances , Campbell, Wouter, Harry , Silbernagel, C., Günther , Vitart, A., Veronique , Rudan, M., Igor , Tofler, Eline, Geoffrey , Navis, L., Gerjan , Destefano, H., Anita , Wright, R., Alan , Chen, L., Ming-Huei , De Craen, C.M., Anton , Worrall, R., Bradford , Rudnicka, H., Alicja , Rumley, F., Ann , Bookman, G.J., Ebony , Psaty, P., Bruce , Chen, P., Fang , Keene, R., Keith , Franco, J., Oscar , Böhm, L., Bernhard , Uitterlinden, J., Andre , Carter, D., Angela , Jukema, D., J. , Sattar, B., Naveed , Bis, C., Joshua , Ikram, M., Mohammad , Sale, J., Michèle , Mcknight, P., Barbara , Fornage, J., Myriam , Ford, J., Ian , Taylor, J., Kent , Slagboom, J., P. , Mcardle, J., Wendy , Hsu, J., Fang-Chi , Franco-Cereceda, J., Anders , Goodall, J., Alison , Yanek, J., Lisa , Furie, J., Karen , Cushman, J., Mary , Hofman, J., Albert , Witteman, J., Jacqueline , Folsom, J., Aaron , Basu, J., Saonli , Matijevic, J., Nena , Van Gilst, J., Wiek , Wilson, J., James , Westendorp, J., Rudi , Kathiresan, J., Sekar , Reilly, J., Muredach , Tracy, J., Russell , Polasek, J., Ozren , Winkelmann, J., Bernhard , Grant, J., Peter , Hillege, J., Hans , Cambien, J., Francois , Stott, J., David , Lowe, J., Gordon , Spector, J., Timothy , Meigs, J., James , Marz, J., Winfried , Eriksson, J., Per , Becker, J., Lewis , Morange, J., Pierre-Emmanuel , Soranzo, J., Nicole , Williams, J., Scott , Hayward, J., Caroline , Van Der Harst, J., Pim , Hamsten, J., Anders , Lowenstein, J., Charles , Strachan, J., David , O’donnell, J., Christopher
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ID: ISSN: 1079-5642 ; DOI: 10.1161/ATVBAHA.113.302088
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recordid: ovid10.1161/ATVBAHA.113.302088
title: Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
format: Article
creator:
  • Huang, E., Jie
  • Huffman, W., Jennifer
  • Yamkauchi, L., Munekazu
  • Trompet, E., Stella
  • Asselbergs, M., Folkert
  • Sabater-Lleal, D., Maria
  • Trégouët, M., David-Alexandre
  • Chen, H., Wei-Min
  • Smith, M.K., Nicholas
  • Kleber, H., Marcus
  • Shin, J., So-Youn
  • Becker, F., Diane
  • Tang, J.M., Weihong
  • Dehghan, B., Abbas
  • Johnson, R., Andrew
  • Truong, B., Vinh
  • Folkersen, M., Lasse
  • Yang, L., Qiong
  • Oudot-Mellkah, H., Tiphaine
  • Buckley, O., Brendan
  • Moore, G., Jason
  • Williams, M., Frances
  • Campbell, Wouter, Harry
  • Silbernagel, C., Günther
  • Vitart, A., Veronique
  • Rudan, M., Igor
  • Tofler, Eline, Geoffrey
  • Navis, L., Gerjan
  • Destefano, H., Anita
  • Wright, R., Alan
  • Chen, L., Ming-Huei
  • De Craen, C.M., Anton
  • Worrall, R., Bradford
  • Rudnicka, H., Alicja
  • Rumley, F., Ann
  • Bookman, G.J., Ebony
  • Psaty, P., Bruce
  • Chen, P., Fang
  • Keene, R., Keith
  • Franco, J., Oscar
  • Böhm, L., Bernhard
  • Uitterlinden, J., Andre
  • Carter, D., Angela
  • Jukema, D., J.
  • Sattar, B., Naveed
  • Bis, C., Joshua
  • Ikram, M., Mohammad
  • Sale, J., Michèle
  • Mcknight, P., Barbara
  • Fornage, J., Myriam
  • Ford, J., Ian
  • Taylor, J., Kent
  • Slagboom, J., P.
  • Mcardle, J., Wendy
  • Hsu, J., Fang-Chi
  • Franco-Cereceda, J., Anders
  • Goodall, J., Alison
  • Yanek, J., Lisa
  • Furie, J., Karen
  • Cushman, J., Mary
  • Hofman, J., Albert
  • Witteman, J., Jacqueline
  • Folsom, J., Aaron
  • Basu, J., Saonli
  • Matijevic, J., Nena
  • Van Gilst, J., Wiek
  • Wilson, J., James
  • Westendorp, J., Rudi
  • Kathiresan, J., Sekar
  • Reilly, J., Muredach
  • Tracy, J., Russell
  • Polasek, J., Ozren
  • Winkelmann, J., Bernhard
  • Grant, J., Peter
  • Hillege, J., Hans
  • Cambien, J., Francois
  • Stott, J., David
  • Lowe, J., Gordon
  • Spector, J., Timothy
  • Meigs, J., James
  • Marz, J., Winfried
  • Eriksson, J., Per
  • Becker, J., Lewis
  • Morange, J., Pierre-Emmanuel
  • Soranzo, J., Nicole
  • Williams, J., Scott
  • Hayward, J., Caroline
  • Van Der Harst, J., Pim
  • Hamsten, J., Anders
  • Lowenstein, J., Charles
  • Strachan, J., David
  • O’donnell, J., Christopher
subjects:
  • Medicine
ispartof: Arteriosclerosis, Thrombosis, and Vascular Biology, 2014, Vol.34(5), pp.1093-1101
description: 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
language:
source:
identifier: ISSN: 1079-5642 ; DOI: 10.1161/ATVBAHA.113.302088
fulltext: fulltext
issn:
  • 1079-5642
  • 10795642
url: Link


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titleGenome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
creatorHuang, E., Jie ; Huffman, W., Jennifer ; Yamkauchi, L., Munekazu ; Trompet, E., Stella ; Asselbergs, M., Folkert ; Sabater-Lleal, D., Maria ; Trégouët, M., David-Alexandre ; Chen, H., Wei-Min ; Smith, M.K., Nicholas ; Kleber, H., Marcus ; Shin, J., So-Youn ; Becker, F., Diane ; Tang, J.M., Weihong ; Dehghan, B., Abbas ; Johnson, R., Andrew ; Truong, B., Vinh ; Folkersen, M., Lasse ; Yang, L., Qiong ; Oudot-Mellkah, H., Tiphaine ; Buckley, O., Brendan ; Moore, G., Jason ; Williams, M., Frances ; Campbell, Wouter, Harry ; Silbernagel, C., Günther ; Vitart, A., Veronique ; Rudan, M., Igor ; Tofler, Eline, Geoffrey ; Navis, L., Gerjan ; Destefano, H., Anita ; Wright, R., Alan ; Chen, L., Ming-Huei ; De Craen, C.M., Anton ; Worrall, R., Bradford ; Rudnicka, H., Alicja ; Rumley, F., Ann ; Bookman, G.J., Ebony ; Psaty, P., Bruce ; Chen, P., Fang ; Keene, R., Keith ; Franco, J., Oscar ; Böhm, L., Bernhard ; Uitterlinden, J., Andre ; Carter, D., Angela ; Jukema, D., J. ; Sattar, B., Naveed ; Bis, C., Joshua ; Ikram, M., Mohammad ; Sale, J., Michèle ; Mcknight, P., Barbara ; Fornage, J., Myriam ; Ford, J., Ian ; Taylor, J., Kent ; Slagboom, J., P. ; Mcardle, J., Wendy ; Hsu, J., Fang-Chi ; Franco-Cereceda, J., Anders ; Goodall, J., Alison ; Yanek, J., Lisa ; Furie, J., Karen ; Cushman, J., Mary ; Hofman, J., Albert ; Witteman, J., Jacqueline ; Folsom, J., Aaron ; Basu, J., Saonli ; Matijevic, J., Nena ; Van Gilst, J., Wiek ; Wilson, J., James ; Westendorp, J., Rudi ; Kathiresan, J., Sekar ; Reilly, J., Muredach ; Tracy, J., Russell ; Polasek, J., Ozren ; Winkelmann, J., Bernhard ; Grant, J., Peter ; Hillege, J., Hans ; Cambien, J., Francois ; Stott, J., David ; Lowe, J., Gordon ; Spector, J., Timothy ; Meigs, J., James ; Marz, J., Winfried ; Eriksson, J., Per ; Becker, J., Lewis ; Morange, J., Pierre-Emmanuel ; Soranzo, J., Nicole ; Williams, J., Scott ; Hayward, J., Caroline ; Van Der Harst, J., Pim ; Hamsten, J., Anders ; Lowenstein, J., Charles ; Strachan, J., David ; O’donnell, J., Christopher
ispartofArteriosclerosis, Thrombosis, and Vascular Biology, 2014, Vol.34(5), pp.1093-1101
identifierISSN: 1079-5642 ; DOI: 10.1161/ATVBAHA.113.302088
descriptionOBJECTIVE—: 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.
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0Huang, E, Jie
1Huffman, W, Jennifer
2Yamkauchi, L, Munekazu
3Trompet, E, Stella
4Asselbergs, M, Folkert
5Sabater-Lleal, D, Maria
6Trégouët, M, David-Alexandre
7Chen, H, Wei-Min
8Smith, M.K, Nicholas
9Kleber, H, Marcus
10Shin, J, So-Youn
11Becker, F, Diane
12Tang, J.M, Weihong
13Dehghan, B, Abbas
14Johnson, R, Andrew
15Truong, B, Vinh
16Folkersen, M, Lasse
17Yang, L, Qiong
18Oudot-Mellkah, H, Tiphaine
19Buckley, O, Brendan
20Moore, G, Jason
21Williams, M, Frances
22Campbell, Wouter, Harry
23Silbernagel, C, Günther
24Vitart, A, Veronique
25Rudan, M, Igor
26Tofler, Eline, Geoffrey
27Navis, L, Gerjan
28DeStefano, H, Anita
29Wright, R, Alan
30Chen, L, Ming-Huei
31de Craen, C.M, Anton
32Worrall, R, Bradford
33Rudnicka, H, Alicja
34Rumley, F, Ann
35Bookman, G.J, Ebony
36Psaty, P, Bruce
37Chen, P, Fang
38Keene, R, Keith
39Franco, J, Oscar
40Böhm, L, Bernhard
41Uitterlinden, J, Andre
42Carter, D, Angela
43Jukema, D, J
44Sattar, B, Naveed
45Bis, C, Joshua
46Ikram, M, Mohammad
47Sale, J, Michèle
48McKnight, P, Barbara
49Fornage, J, Myriam
50Ford, J, Ian
51Taylor, J, Kent
52Slagboom, J, P
53McArdle, J, Wendy
54Hsu, J, Fang-Chi
55Franco-Cereceda, J, Anders
56Goodall, J, Alison
57Yanek, J, Lisa
58Furie, J, Karen
59Cushman, J, Mary
60Hofman, J, Albert
61Witteman, J, Jacqueline
62Folsom, J, Aaron
63Basu, J, Saonli
64Matijevic, J, Nena
65van Gilst, J, Wiek
66Wilson, J, James
67Westendorp, J, Rudi
68Kathiresan, J, Sekar
69Reilly, J, Muredach
70Tracy, J, Russell
71Polasek, J, Ozren
72Winkelmann, J, Bernhard
73Grant, J, Peter
74Hillege, J, Hans
75Cambien, J, Francois
76Stott, J, David
77Lowe, J, Gordon
78Spector, J, Timothy
79Meigs, J, James
80Marz, J, Winfried
81Eriksson, J, Per
82Becker, J, Lewis
83Morange, J, Pierre-Emmanuel
84Soranzo, J, Nicole
85Williams, J, Scott
86Hayward, J, Caroline
87van der Harst, J, Pim
88Hamsten, J, Anders
89Lowenstein, J, Charles
90Strachan, J, David
91O’Donnell, J, Christopher
titleGenome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
descriptionOBJECTIVE—: 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.
general
010.1161/ATVBAHA.113.302088
1© 2014 American Heart Association, Inc.
2Lippincott Williams & Wilkins - Journals
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titleGenome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
authorHuang, E., Jie ; Huffman, W., Jennifer ; Yamkauchi, L., Munekazu ; Trompet, E., Stella ; Asselbergs, M., Folkert ; Sabater-Lleal, D., Maria ; Trégouët, M., David-Alexandre ; Chen, H., Wei-Min ; Smith, M.K., Nicholas ; Kleber, H., Marcus ; Shin, J., So-Youn ; Becker, F., Diane ; Tang, J.M., Weihong ; Dehghan, B., Abbas ; Johnson, R., Andrew ; Truong, B., Vinh ; Folkersen, M., Lasse ; Yang, L., Qiong ; Oudot-Mellkah, H., Tiphaine ; Buckley, O., Brendan ; Moore, G., Jason ; Williams, M., Frances ; Campbell, Wouter, Harry ; Silbernagel, C., Günther ; Vitart, A., Veronique ; Rudan, M., Igor ; Tofler, Eline, Geoffrey ; Navis, L., Gerjan ; Destefano, H., Anita ; Wright, R., Alan ; Chen, L., Ming-Huei ; De Craen, C.M., Anton ; Worrall, R., Bradford ; Rudnicka, H., Alicja ; Rumley, F., Ann ; Bookman, G.J., Ebony ; Psaty, P., Bruce ; Chen, P., Fang ; Keene, R., Keith ; Franco, J., Oscar ; Böhm, L., Bernhard ; Uitterlinden, J., Andre ; Carter, D., Angela ; Jukema, D., J. ; Sattar, B., Naveed ; Bis, C., Joshua ; Ikram, M., Mohammad ; Sale, J., Michèle ; Mcknight, P., Barbara ; Fornage, J., Myriam ; Ford, J., Ian ; Taylor, J., Kent ; Slagboom, J., P. ; Mcardle, J., Wendy ; Hsu, J., Fang-Chi ; Franco-Cereceda, J., Anders ; Goodall, J., Alison ; Yanek, J., Lisa ; Furie, J., Karen ; Cushman, J., Mary ; Hofman, J., Albert ; Witteman, J., Jacqueline ; Folsom, J., Aaron ; Basu, J., Saonli ; Matijevic, J., Nena ; Van Gilst, J., Wiek ; Wilson, J., James ; Westendorp, J., Rudi ; Kathiresan, J., Sekar ; Reilly, J., Muredach ; Tracy, J., Russell ; Polasek, J., Ozren ; Winkelmann, J., Bernhard ; Grant, J., Peter ; Hillege, J., Hans ; Cambien, J., Francois ; Stott, J., David ; Lowe, J., Gordon ; Spector, J., Timothy ; Meigs, J., James ; Marz, J., Winfried ; Eriksson, J., Per ; Becker, J., Lewis ; Morange, J., Pierre-Emmanuel ; Soranzo, J., Nicole ; Williams, J., Scott ; Hayward, J., Caroline ; Van Der Harst, J., Pim ; Hamsten, J., Anders ; Lowenstein, J., Charles ; Strachan, J., David ; O’donnell, J., Christopher
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0Huang, E., Jie
1Huffman, W., Jennifer
2Yamkauchi, L., Munekazu
3Trompet, E., Stella
4Asselbergs, M., Folkert
5Sabater-Lleal, D., Maria
6Trégouët, M., David-Alexandre
7Chen, H., Wei-Min
8Smith, M.K., Nicholas
9Kleber, H., Marcus
10Shin, J., So-Youn
11Becker, F., Diane
12Tang, J.M., Weihong
13Dehghan, B., Abbas
14Johnson, R., Andrew
15Truong, B., Vinh
16Folkersen, M., Lasse
17Yang, L., Qiong
18Oudot-Mellkah, H., Tiphaine
19Buckley, O., Brendan
20Moore, G., Jason
21Williams, M., Frances
22Campbell, Wouter, Harry
23Silbernagel, C., Günther
24Vitart, A., Veronique
25Rudan, M., Igor
26Tofler, Eline, Geoffrey
27Navis, L., Gerjan
28Destefano, H., Anita
29Wright, R., Alan
30Chen, L., Ming-Huei
31De Craen, C.M., Anton
32Worrall, R., Bradford
33Rudnicka, H., Alicja
34Rumley, F., Ann
35Bookman, G.J., Ebony
36Psaty, P., Bruce
37Chen, P., Fang
38Keene, R., Keith
39Franco, J., Oscar
40Böhm, L., Bernhard
41Uitterlinden, J., Andre
42Carter, D., Angela
43Jukema, D., J.
44Sattar, B., Naveed
45Bis, C., Joshua
46Ikram, M., Mohammad
47Sale, J., Michèle
48Mcknight, P., Barbara
49Fornage, J., Myriam
50Ford, J., Ian
51Taylor, J., Kent
52Slagboom, J., P.
53Mcardle, J., Wendy
54Hsu, J., Fang-Chi
55Franco-Cereceda, J., Anders
56Goodall, J., Alison
57Yanek, J., Lisa
58Furie, J., Karen
59Cushman, J., Mary
60Hofman, J., Albert
61Witteman, J., Jacqueline
62Folsom, J., Aaron
63Basu, J., Saonli
64Matijevic, J., Nena
65Van Gilst, J., Wiek
66Wilson, J., James
67Westendorp, J., Rudi
68Kathiresan, J., Sekar
69Reilly, J., Muredach
70Tracy, J., Russell
71Polasek, J., Ozren
72Winkelmann, J., Bernhard
73Grant, J., Peter
74Hillege, J., Hans
75Cambien, J., Francois
76Stott, J., David
77Lowe, J., Gordon
78Spector, J., Timothy
79Meigs, J., James
80Marz, J., Winfried
81Eriksson, J., Per
82Becker, J., Lewis
83Morange, J., Pierre-Emmanuel
84Soranzo, J., Nicole
85Williams, J., Scott
86Hayward, J., Caroline
87Van Der Harst, J., Pim
88Hamsten, J., Anders
89Lowenstein, J., Charles
90Strachan, J., David
91O’donnell, J., Christopher
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35Ebony
36Bruce
37Fang
38Keith
39Oscar
40Bernhard
41Andre
42Angela
43J.
44Naveed
45Joshua
46Mohammad
47Michèle
48Barbara
49Myriam
50Ian
51Kent
52P.
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55Anders
56Alison
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63Saonli
64Nena
65Wiek
66James
67Rudi
68Sekar
69Muredach
70Russell
71Ozren
72Peter
73Hans
74Francois
75David
76Gordon
77Timothy
78Winfried
79Per
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81Pierre-Emmanuel
82Nicole
83Scott
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6M.K.
7J.
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10B.
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atitleGenome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
jtitleArteriosclerosis, Thrombosis, and Vascular Biology
risdate201405
volume34
issue5
spage1093
epage1101
pages1093-1101
issn1079-5642
formatjournal
genrearticle
ristypeJOUR
abstractOBJECTIVE—: 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.
pub© 2014 American Heart Association, Inc.
doi10.1161/ATVBAHA.113.302088
eissn15244636
date2014-05