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

Authors :
Huang J
Huffman JE
Yamakuchi 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 FM
Campbell H
Silbernagel G
Vitart V
Rudan I
Tofler GH
Navis GJ
Destefano A
Wright AF
Chen MH
de Craen AJ
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 JC
Folsom AR
Basu S
Matijevic N
van Gilst WH
Wilson JF
Westendorp RG
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
Source :
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2014 May; Vol. 34 (5), pp. 1093-101. Date of Electronic Publication: 2014 Feb 27.
Publication Year :
2014

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.<br />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(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-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=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-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.<br />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.

Details

Language :
English
ISSN :
1524-4636
Volume :
34
Issue :
5
Database :
MEDLINE
Journal :
Arteriosclerosis, thrombosis, and vascular biology
Publication Type :
Academic Journal
Accession number :
24578379
Full Text :
https://doi.org/10.1161/ATVBAHA.113.302088