期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 5, 页码 1093-1101出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.302088
关键词
fibrinolysis; genome-wide association study; hemostasis; meta-analysis; tissue plasminogen activator
资金
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]
- Swedish Research Council [12660]
- Stockholm County Council [20090077]
- Swedish Heart-Lung Foundation [20090541, 8691]
- European Commission (FAD) [Health F2 2008 200647]
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02, 076113/B/04/Z]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Human Genome Research Institute (NHGRI)
- National Institute of Child Health and Human Development (NICHD)
- Juvenile Diabetes Research Foundation International (JDRF)
- Juvenile Diabetes Research Foundation International
- Wellcome Trust
- National Institute for Health Research (NIHR)
- Cambridge Biomedical Research Centre
- Wellcome Trust Strategic Award [079895]
- EU [018996, LSHM-CT-2006-037593]
- French Ministry of Research
- NHLBI [HHSN268201200036C, N01HC85239, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, N01-HC-35129, N01 HC-15103, N01-HC-75150, N01-HC-45133]
- National Institute of Neurological Disorders and Stroke NINDS
- National Institute on Aging (NIA) [AG023629]
- National Center for Research Resources [UL1RR033176]
- National Center for Advancing Translational Sciences, Clinical & Translational Science Institute [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease grant [DK063491]
- Medical Research Council UK
- Ministry of Science, Education, and Sport of the Republic of Croatia [108-10803150302]
- EU 6th Framework Programme EUROSPAN project [LSHG-CT-2006-018947]
- NHLBI's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140]
- GeneSTAR from the National Institutes of Health (NIH) [1U01 HL072518, R01 HL59684]
- Johns Hopkins University School of Medicine General Clinical Research Center
- NIH [M01 RR00052, LM010098, HL65234, HL67466, RR018787, P01 HL56091, R01 HL074061, R01 HL78635, P01 HL65608]
- Knut and Alice Wallenberg Foundation
- Swedish Heart-Lung Foundation
- Torsten and Ragnar Sderberg Foundation
- Strategic Cardiovascular Program of Karolinska Institutet
- Stockholm County Council
- Foundation for Strategic Research
- Marie Curie Intra European Fellowship within the EU [PIEF-GA-2009-252361]
- EU 6th Framework Programme [LSHG-CT-2006-018947, LSHM-CT-2004-503485]
- EU 7th Framework Programme (Atheroremo) [201668]
- EU 7th Framework Programme (RiskyCAD) [305739]
- Program Hospitalier de Recherche Clinique
- Fondation pour la Recherche Medicale
- La Region Ile de France (CODDIM)
- Genomic Network of the Pierre and Marie Curie University, Paris
- Chief Scientist Office of the Scottish Government
- Royal Society
- Wellcome Trust Clinical Research Facility in Edinburgh, United Kingdom
- Dutch Kidney Foundation [E033]
- Netherlands Heart Foundation [2006B140, 2006T003, 2001 D 032]
- EU project grant GENECURE [2006037697]
- NWO VENI [91676170]
- Dutch Inter University Cardiology Institute Netherlands (ICIN)
- Netherlands Organization for Health Research and Development (ZonMw) [90700342]
- Bristol-Myers Squibb
- 7th Framework Programme of the European commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- Scottish Executive Chief Scientist Office, Health Services Research Committee [CZG/4/306]
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Organization for ZonMw
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission
- Municipality of Rotterdam
- NWO [175.010.2005.011, 911-03-012, 918-76-619, 916.12.154]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]
- EUR Fellowship
- European Community [005268]
- ENGAGE project [HEALTH-F4-2007-201413]
- FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- Department of Health via the NIHR comprehensive Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council (BBSRC) project [G20234]
- National Eye Institute via an NIH/Center for Inherited Disease Research (CIDR) genotyping project
- Oak Foundation
- American Heart Association (AHA) [EIG 0140210N]
- Paul N. Yu Professorship
- AHA [0835446N]
- National Human Genome Research Institute (NHGRI) [U01 HG005160]
- NIH
- United States Public Health Service [R01 NS34447]
- NINDS/NIH
- ARIC [U01 HL096917, R01-HL093029]
- NIA [AG-023629, AG-15928, AG-20098, AG-027058, NS17950, AG08122, AG033193]
- NINDS
- [U01 DK062418]
- Grants-in-Aid for Scientific Research [26293130] Funding Source: KAKEN
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [G0000934, MC_PC_U127561128] Funding Source: researchfish
- MRC [MC_PC_U127561128, G0000934] Funding Source: UKRI
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.
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