Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.
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DOI：
10.1161/atvbaha.113.302088
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发表时间：
2014-05
期刊：
影响因子：
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通讯作者：
CHARGE Consortium Hemostatic Factor Working Group
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作者：
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;Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group;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;CARDIoGRAM Consortium;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;CHARGE Consortium Hemostatic Factor Working Group
组织纤溶酶原激活物(TPA)是一种丝氨酸蛋白酶，催化纤溶酶原转化为纤溶酶，是内源性纤溶的主要酶。在一些人群中，血浆tPA水平升高与心肌梗死和其他心血管疾病(CVD)有关。我们进行了全基因组关联研究的荟萃分析，以确定循环中tPA水平的新相关性。14项采用tPA指标的队列研究(N=26,929)参与了荟萃分析。3个基因座与血浆tPA水平显著相关(P<；5.0×10−8)。第一个基因座位于6q24.3上，位于STXBP5内的领先单核苷酸多态(rs9399599，P=2.9×10−14)。第二个基因座位于8p11.21。Pad SNP(rs3136739，P=1.3×10−9)是POLB的内含子，与tPA编码基因平台的距离小于200kb。我们在中度LD中发现了一个非同义SNP(Rs2020921)，在Plat第5外显子中发现了rs3136739(R2=0.50)(P=2.0×10−8)。第三个基因座位于12q24.33上，位于STX2内含子7内含子内的前导SNP(rs7301826，P=1.0×10−9)。我们进一步发现了STXBP5和STX2中的铅SNPs与各自转录本的表达水平相关的证据。在体外细胞研究中，沉默STXBP5减少血管内皮细胞释放tPA，而沉默STX2增加tPA释放。通过电子计算机搜索，我们没有发现这三个铅SNP与冠状动脉疾病或中风之间的关联。我们确定了三个与循环tPA水平相关的基因座，即Plat区、STXBP5和STX2。我们的功能研究表明，STXBP5和STX2在调节tPA释放方面发挥了新的作用。
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 (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA. 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 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 less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 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 association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke. We identified three 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.