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

J Huang; JE Huffman; M Yamkauchi; S Trompet; FW Asselbergs; M Sabater-Lleal; DA Tregouet; WM Chen; NL Smith; ME Kleber; SY Shin; DM Becker; WH Tang; Abbas Dehghan; AD Johnson; V Truong; L Folkersen; Q Yang; T Oudot-Mellkah; BM Buckley; JH Moore; FMK Williams; H Campbell; G Silbernagel; V Vitart; I Rudan; GH Tofler; GJ Navis; A DeStefano; AF Wright; MH Chen; AJM de Craen; BB Worrall; AR Rudnicka; A Rumley; EB Bookman; BM Psaty; F Chen; KL Keene; OH Franco Duran; BO Bohm; André Uitterlinden; AM Carter; JW Jukema; N Sattar; JC Bis; Arfan Ikram; MM Sale; B McKnight; M Fornage; I Ford; K Taylor; PE (Eline) Slagboom; WL McArdle; FC Hsu; A Franco-Cereceda; AH Goodall; LR Yanek; KL Furie; M Cushman; Bert Hofman; JCM Witteman; AR Folsom; Sreya Basu; N Matijevic; WH van Gilst; JF Wilson; RGJ Westendorp; S Kathiresan; MP Reilly; RP Tracy; O Polasek; BR Winkelmann; PJ Grant; HL Hillege; F Cambien; DJ Stott; GD Lowe; TD Spector; JB Meigs; W Marz; P Eriksson; LC Becker; PE Morange; N Soranzo; SM Williams; C Hayward; P van der Harst; A Hamsten; CJ Lowenstein; DP Strachan; CJ 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

J Huang, JE Huffman, M Yamkauchi, S Trompet, FW Asselbergs, M Sabater-Lleal, DA Tregouet, WM Chen, NL Smith, ME Kleber, SY Shin, DM Becker, WH Tang, Abbas Dehghan, AD Johnson, V Truong, L Folkersen, Q Yang, T Oudot-Mellkah, BM BuckleyJH Moore, FMK Williams, H Campbell, G Silbernagel, V Vitart, I Rudan, GH Tofler, GJ Navis, A DeStefano, AF Wright, MH Chen, AJM de Craen, BB Worrall, AR Rudnicka, A Rumley, EB Bookman, BM Psaty, F Chen, KL Keene, OH Franco Duran, BO Bohm, André Uitterlinden, AM Carter, JW Jukema, N Sattar, JC Bis, Arfan Ikram, MM Sale, B McKnight, M Fornage, I Ford, K Taylor, PE (Eline) Slagboom, WL McArdle, FC Hsu, A Franco-Cereceda, AH Goodall, LR Yanek, KL Furie, M Cushman, Bert Hofman, JCM Witteman, AR Folsom, Sreya Basu, N Matijevic, WH van Gilst, JF Wilson, RGJ Westendorp, S Kathiresan, MP Reilly, RP Tracy, O Polasek, BR Winkelmann, PJ Grant, HL Hillege, F Cambien, DJ Stott, GD Lowe, TD Spector, JB Meigs, W Marz, P Eriksson, LC Becker, PE Morange, N Soranzo, SM Williams, C Hayward, P van der Harst, A Hamsten, CJ Lowenstein, DP Strachan, CJ O'Donnell

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

33 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<5.0x10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9x10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3x10(-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=2.0x10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0x10(-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. 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	Undefined/Unknown
Pages (from-to)	1093-1101
Number of pages	9
Journal	Arteriosclerosis Thrombosis & Vascular Biology
Volume	34
Issue number	5
DOIs	https://doi.org/10.1161/ATVBAHA.113.302088
Publication status	Published - 2014

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Cite this

Huang, J., Huffman, JE., Yamkauchi, M., Trompet, S., Asselbergs, FW., Sabater-Lleal, M., Tregouet, DA., Chen, WM., Smith, NL., Kleber, ME., Shin, SY., Becker, DM., Tang, WH., Dehghan, A., Johnson, AD., Truong, V., Folkersen, L., Yang, Q., Oudot-Mellkah, T., ... 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 & Vascular Biology, 34(5), 1093-1101. https://doi.org/10.1161/ATVBAHA.113.302088

@article{70e8447277134f899850b19786dc528f,

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<5.0x10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9x10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3x10(-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=2.0x10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0x10(-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. 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.",

author = "J Huang and JE Huffman and M Yamkauchi and S Trompet and FW Asselbergs and M Sabater-Lleal and DA Tregouet and WM Chen and NL Smith and ME Kleber and SY Shin and DM Becker and WH Tang and Abbas Dehghan and AD Johnson and V Truong and L Folkersen and Q Yang and T Oudot-Mellkah and BM Buckley and JH Moore and FMK Williams and H Campbell and G Silbernagel and V Vitart and I Rudan and GH Tofler and GJ Navis and A DeStefano and AF Wright and MH Chen and {de Craen}, AJM and BB Worrall and AR Rudnicka and A Rumley and EB Bookman and BM Psaty and F Chen and KL Keene and {Franco Duran}, OH and BO Bohm and Andr{\'e} Uitterlinden and AM Carter and JW Jukema and N Sattar and JC Bis and Arfan Ikram and MM Sale and B McKnight and M Fornage and I Ford and K Taylor and Slagboom, {PE (Eline)} and WL McArdle and FC Hsu and A Franco-Cereceda and AH Goodall and LR Yanek and KL Furie and M Cushman and Bert Hofman and JCM Witteman and AR Folsom and Sreya Basu and N Matijevic and {van Gilst}, WH and JF Wilson and RGJ Westendorp and S Kathiresan and MP Reilly and RP Tracy and O Polasek and BR Winkelmann and PJ Grant and HL Hillege and F Cambien and DJ Stott and GD Lowe and TD Spector and JB Meigs and W Marz and P Eriksson and LC Becker and PE Morange and N Soranzo and SM Williams and C Hayward and {van der Harst}, P and A Hamsten and CJ Lowenstein and DP Strachan and CJ O'Donnell",

year = "2014",

doi = "10.1161/ATVBAHA.113.302088",

language = "Undefined/Unknown",

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, DA, Chen, WM, Smith, NL, Kleber, ME, Shin, SY, Becker, DM, Tang, WH, 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 Duran, OH, Bohm, BO, Uitterlinden, A, Carter, AM, Jukema, JW, Sattar, N, Bis, JC, Ikram, A, 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, B, 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 & Vascular Biology, vol. 34, no. 5, pp. 1093-1101. https://doi.org/10.1161/ATVBAHA.113.302088

TY - JOUR

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

AU - Huang, J

AU - Huffman, JE

AU - Yamkauchi, M

AU - Trompet, S

AU - Asselbergs, FW

AU - Sabater-Lleal, M

AU - Tregouet, DA

AU - Chen, WM

AU - Smith, NL

AU - Kleber, ME

AU - Shin, SY

AU - Becker, DM

AU - Tang, WH

AU - Dehghan, Abbas

AU - Johnson, AD

AU - Truong, V

AU - Folkersen, L

AU - Yang, Q

AU - Oudot-Mellkah, T

AU - Buckley, BM

AU - Moore, JH

AU - Williams, FMK

AU - Campbell, H

AU - Silbernagel, G

AU - Vitart, V

AU - Rudan, I

AU - Tofler, GH

AU - Navis, GJ

AU - DeStefano, A

AU - Wright, AF

AU - Chen, MH

AU - de Craen, AJM

AU - Worrall, BB

AU - Rudnicka, AR

AU - Rumley, A

AU - Bookman, EB

AU - Psaty, BM

AU - Chen, F

AU - Keene, KL

AU - Franco Duran, OH

AU - Bohm, BO

AU - Uitterlinden, André

AU - Carter, AM

AU - Jukema, JW

AU - Sattar, N

AU - Bis, JC

AU - Ikram, Arfan

AU - Sale, MM

AU - McKnight, B

AU - Fornage, M

AU - Ford, I

AU - Taylor, K

AU - Slagboom, PE (Eline)

AU - McArdle, WL

AU - Hsu, FC

AU - Franco-Cereceda, A

AU - Goodall, AH

AU - Yanek, LR

AU - Furie, KL

AU - Cushman, M

AU - Hofman, Bert

AU - Witteman, JCM

AU - Folsom, AR

AU - Basu, Sreya

AU - Matijevic, N

AU - van Gilst, WH

AU - Wilson, JF

AU - Westendorp, RGJ

AU - Kathiresan, S

AU - Reilly, MP

AU - Tracy, RP

AU - Polasek, O

AU - Winkelmann, BR

AU - Grant, PJ

AU - Hillege, HL

AU - Cambien, F

AU - Stott, DJ

AU - Lowe, GD

AU - Spector, TD

AU - Meigs, JB

AU - Marz, W

AU - Eriksson, P

AU - Becker, LC

AU - Morange, PE

AU - Soranzo, N

AU - Williams, SM

AU - Hayward, C

AU - van der Harst, P

AU - Hamsten, A

AU - Lowenstein, CJ

AU - Strachan, DP

AU - O'Donnell, CJ

PY - 2014

Y1 - 2014

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<5.0x10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9x10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3x10(-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=2.0x10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0x10(-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. 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<5.0x10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9x10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3x10(-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=2.0x10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0x10(-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. 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.

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 -