1. Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
- Author
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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, and O'Donnell CJ
- Subjects
- Aged, Cells, Cultured, Coronary Artery Disease blood, Coronary Artery Disease enzymology, Coronary Artery Disease genetics, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins genetics, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins genetics, Risk Factors, Stroke blood, Stroke enzymology, Stroke genetics, Syntaxin 1 genetics, Tissue Plasminogen Activator genetics, Transfection, United States, Up-Regulation, Endothelial Cells enzymology, Nerve Tissue Proteins metabolism, R-SNARE Proteins metabolism, Syntaxin 1 metabolism, Tissue Plasminogen Activator blood
- 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(-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., 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.
- Published
- 2014
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