期刊
THROMBOSIS AND HAEMOSTASIS
卷 110, 期 5, 页码 995-1003出版社
GEORG THIEME VERLAG KG
DOI: 10.1160/TH13-02-0087
关键词
Haemostasis; thrombosis; HumanCVD; clotting factors; genetic association
资金
- BHF [PG/07/131/24254, PG/07/133/24260, RG/08/008, SP/07/007/23671]
- Department of Health Policy Research Programme (England)
- MRC [G1000427]
- WHII [PG08/008]
- UCL Genetics Institute
- National Heart Lung and Blood Institute (NHLBI) [HL36310]
- Medical Research Council
- Economic and Social-Research Council
- British Heart Foundation
- Health and Safety Executive
- Department of Health
- National Institute-on Aging, US, NIH [AG13196]
- Agency for Health Care Policy Research [HS06516]
- Catherine T MacArthur Foundation Research Networks on Successful Midlife Development
- Socio-economic Status and Health
- British Heart Foundation [PG/09/022/26739, RG/08/008/25291] Funding Source: researchfish
- Economic and Social Research Council [ES/J023299/1] Funding Source: researchfish
- Medical Research Council [G1000427, MC_UU_12013/8, MR/K013351/1] Funding Source: researchfish
- ESRC [ES/J023299/1] Funding Source: UKRI
- MRC [MR/K013351/1, MC_UU_12013/8, G1000427] Funding Source: UKRI
Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGAIFGBIFGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10(-6)), GCKR (rs1260326, p=1.63x10(-6)), ZNF259-APOA5 (rs651821, p=7.17x10(-6)) with plasma viscosity; and at CSF1 (rs333948, p=8.88x10(-6)) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10(-7)) and plasma viscosity (p=1.63x10(-6)), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10(-2)) and plasma viscosity (p<1.00x10(-6)).Triglyceride associated variants were over-represented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation.
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