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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(-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.

SUBMITTER: Huang J

PROVIDER: S-EPMC4009733 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Huang Jie J Huffman Jennifer E JE Yamakuchi Munekazu M Trompet Stella S Asselbergs Folkert W FW Sabater-Lleal Maria M Trégouët David-Alexandre DA Chen Wei-Min WM Smith Nicholas L NL Kleber Marcus E ME Shin So-Youn SY Becker Diane M DM Tang Weihong W Dehghan Abbas A Johnson Andrew D AD Truong Vinh V Folkersen Lasse L Yang Qiong Q Oudot-Mellkah Tiphaine T Buckley Brendan M BM Moore Jason H JH Williams Frances M K FM Campbell Harry H Silbernagel Günther G Vitart Veronique V Rudan Igor I Tofler Geoffrey H GH Navis Gerjan J GJ Destefano Anita A Wright Alan F AF Chen Ming-Huei MH de Craen Anton J M AJ Worrall Bradford B BB Rudnicka Alicja R AR Rumley Ann A Bookman Ebony B EB Psaty Bruce M BM Chen Fang F Keene Keith L KL Franco Oscar H OH Böhm Bernhard O BO Uitterlinden Andre G AG Carter Angela M AM Jukema J Wouter JW Sattar Naveed N Bis Joshua C JC Bis Joshua C JC Ikram Mohammad A MA Sale Michèle M MM McKnight Barbara B Fornage Myriam M Ford Ian I Taylor Kent K Slagboom P Eline PE McArdle Wendy L WL Hsu Fang-Chi FC Franco-Cereceda Anders A Goodall Alison H AH Yanek Lisa R LR Furie Karen L KL Cushman Mary M Hofman Albert A Witteman Jacqueline C M JC Folsom Aaron R AR Basu Saonli S Matijevic Nena N van Gilst Wiek H WH Wilson James F JF Westendorp Rudi G J RG Kathiresan Sekar S Reilly Muredach P MP Tracy Russell P RP Polasek Ozren O Winkelmann Bernhard R BR Grant Peter J PJ Hillege Hans L HL Cambien Francois F Stott David J DJ Lowe Gordon D GD Spector Timothy D TD Meigs James B JB Marz Winfried W Eriksson Per P Becker Lewis C LC Morange Pierre-Emmanuel PE Soranzo Nicole N Williams Scott M SM Hayward Caroline C van der Harst Pim P Hamsten Anders A Lowenstein Charles J CJ Strachan David P DP O'Donnell Christopher J CJ

Arteriosclerosis, thrombosis, and vascular biology 20140227 5

<h4>Objective</h4>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.<h4>Approach and results</h4>Fourteen cohort studies with tPA ...[more]

PMID: 24578379

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Project description:Background & Aims:Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection. Methods:Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls. Results:High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection. Conclusion:Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery. Lay summary:Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates.

Dataset Information

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

Publications

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

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