期刊
CIRCULATION
卷 121, 期 12, 页码 1382-U45出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.109.869156
关键词
genetic variation; factor VII; factor VIII; von Willebrand factor; epidemiology; meta-analysis; thrombosis; hemostasis
资金
- NHLBI [N01-HC-55015, N01-HC55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01-HL-087641, R01-HL59367]
- National Human Genome Research Institute [U01-HG-004402]
- National Institutes of Health (NIH) [HHSN268200625226C, UL1-RR-025005]
- Medical Research Council [G0000934]
- Wellcome Trust [068545/Z/02]
- National Institute of Neurological Disorders and Stroke
- National Center for Research Resources [M01-RR00425]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK063491, K24 DK080140]
- NHLBI's FHS [N01-HC-25195, N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012]
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Research Institute for Diseases in the Elderly (RIDE) [94800022]
- Netherlands Genomics Initiative (NGI)/NWO [050-060-810]
- Wellcome Trust
- European Community [FP-6/2005-2008]
- FP7/2007-2013 [HEALTH-F4-2007-201413]
- FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- Department of Health via a National Institute for Health Research (NIHR)
- Biotechnology and Biological Sciences Research Council [G20234]
- National Eye Institute via an NIH/Center for Inherited Disease Research
- Medical Research Council UK
- Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]
- European Union [LSHG-CT-2006-018947]
- Chief Scientist Office of the Scottish Government
- Royal Society
- EC [LSHM-CT-2007-037273]
- Swedish Research Council [8691]
- Knut and Alice Wallenberg Foundation
- Swedish Heart-Lung Foundation
- Leducq Foundation, Paris
- Stockholm County Council [560283]
- AstraZeneca
- Sanofi-Aventis
- GlaxoSmithKline
- NHLBI contracts [R01-HL-086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL 087652, HL073410, HL095080]
- Biotechnology and Biological Sciences Research Council [G20234/2] Funding Source: researchfish
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [G0000934, MC_U127561128, MC_qA137934] Funding Source: researchfish
- MRC [MC_U127561128, G0000934, MC_qA137934] Funding Source: UKRI
Background-Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. Methods and Results-The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0X10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2X10(-24)), 4q25 (3.6X10(-12)), 11q12 (2.0X10(-10)), 13q34 (9.0X10(-259)), and 20q11.2 (5.7X10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2X10(-22)), 8p21 (1.3X10(-16)), 9q34 (<5.0X10(-324)), 12p13 (1.7X10(-32)), 12q23 (7.3X10(-10)), 12q24.3 (3.8X10(-11)), 14q32 (2.3X10(-10)), and 19p13.2 (1.3X10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. Conclusions-New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders. (Circulation. 2010; 121: 1382-1392.)
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