N C Olson1,2, L M Raffield3, L A Lange4, E M Lange4, W T Longstreth5,6, G Chauhan7,8,9, S Debette7,8,10,11,12, S Seshadri11,12, A P Reiner10, R P Tracy1,2,13. 1. Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA. 2. Cardiovascular Research Institute of Vermont, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA. 3. Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA. 4. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 5. Department of Neurology, University of Washington, Seattle, WA, USA. 6. Department of Epidemiology, University of Washington, Seattle, WA, USA. 7. INSERM U1219 Neuroepidemiology, Bordeaux, France. 8. University of Bordeaux, Bordeaux, France. 9. Centre for Brain Research, Indian Institute of Science, Bangalore, India. 10. Department of Neurology, Bordeaux University Hospital, Bordeaux, France. 11. Department of Neurology, Boston University School of Medicine, Boston, MA, USA. 12. National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA. 13. Department of Biochemistry, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
Abstract
ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL-1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL-1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.
ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL-1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL-1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHSparticipants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.
Authors: J A Cooper; G J Miller; K A Bauer; J H Morrissey; T W Meade; D J Howarth; S Barzegar; J P Mitchell; R D Rosenberg Journal: Circulation Date: 2000-12-05 Impact factor: 29.690
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: H M Ghaddar; A R Folsom; N Aleksic; L B Hearne; L E Chambless; J H Morrissey; K K Wu Journal: Circulation Date: 1998 Dec 22-29 Impact factor: 29.690
Authors: N A Zakai; L Lange; W T Longstreth; E S O'Meara; J L Kelley; M Fornage; D Nikerson; M Cushman; A P Reiner Journal: J Thromb Haemost Date: 2011-02 Impact factor: 5.824
Authors: N Martinelli; D Girelli; M Baroni; P Guarini; M Sandri; B Lunghi; F Tosi; A Branchini; F Sartori; B Woodhams; F Bernardi; O Olivieri Journal: J Thromb Haemost Date: 2016-03-14 Impact factor: 5.824
Authors: Bruce M Psaty; Christopher J O'Donnell; Vilmundur Gudnason; Kathryn L Lunetta; Aaron R Folsom; Jerome I Rotter; André G Uitterlinden; Tamara B Harris; Jacqueline C M Witteman; Eric Boerwinkle Journal: Circ Cardiovasc Genet Date: 2009-02
Authors: Nicholas L Smith; Ming-Huei Chen; Abbas Dehghan; David P Strachan; Saonli Basu; Nicole Soranzo; Caroline Hayward; Igor Rudan; Maria Sabater-Lleal; Joshua C Bis; Moniek P M de Maat; Ann Rumley; Xiaoxiao Kong; Qiong Yang; Frances M K Williams; Veronique Vitart; Harry Campbell; Anders Mälarstig; Kerri L Wiggins; Cornelia M Van Duijn; Wendy L McArdle; James S Pankow; Andrew D Johnson; Angela Silveira; Barbara McKnight; Andre G Uitterlinden; Nena Aleksic; James B Meigs; Annette Peters; Wolfgang Koenig; Mary Cushman; Sekar Kathiresan; Jerome I Rotter; Edwin G Bovill; Albert Hofman; Eric Boerwinkle; Geoffrey H Tofler; John F Peden; Bruce M Psaty; Frank Leebeek; Aaron R Folsom; Martin G Larson; Timothy D Spector; Alan F Wright; James F Wilson; Anders Hamsten; Thomas Lumley; Jacqueline C M Witteman; Weihong Tang; Christopher J O'Donnell Journal: Circulation Date: 2010-03-15 Impact factor: 29.690
Authors: Jennifer E Huffman; Paul S de Vries; Alanna C Morrison; Maria Sabater-Lleal; Tim Kacprowski; Paul L Auer; Jennifer A Brody; Daniel I Chasman; Ming-Huei Chen; Xiuqing Guo; Li-An Lin; Riccardo E Marioni; Martina Müller-Nurasyid; Lisa R Yanek; Nathan Pankratz; Megan L Grove; Moniek P M de Maat; Mary Cushman; Kerri L Wiggins; Lihong Qi; Bengt Sennblad; Sarah E Harris; Ozren Polasek; Helene Riess; Fernando Rivadeneira; Lynda M Rose; Anuj Goel; Kent D Taylor; Alexander Teumer; André G Uitterlinden; Dhananjay Vaidya; Jie Yao; Weihong Tang; Daniel Levy; Melanie Waldenberger; Diane M Becker; Aaron R Folsom; Franco Giulianini; Andreas Greinacher; Albert Hofman; Chiang-Ching Huang; Charles Kooperberg; Angela Silveira; John M Starr; Konstantin Strauch; Rona J Strawbridge; Alan F Wright; Barbara McKnight; Oscar H Franco; Neil Zakai; Rasika A Mathias; Bruce M Psaty; Paul M Ridker; Geoffrey H Tofler; Uwe Völker; Hugh Watkins; Myriam Fornage; Anders Hamsten; Ian J Deary; Eric Boerwinkle; Wolfgang Koenig; Jerome I Rotter; Caroline Hayward; Abbas Dehghan; Alex P Reiner; Christopher J O'Donnell; Nicholas L Smith Journal: Blood Date: 2015-06-23 Impact factor: 22.113
Authors: Gerard Temprano-Sagrera; Colleen M Sitlani; William P Bone; Miguel Martin-Bornez; Benjamin F Voight; Alanna C Morrison; Scott M Damrauer; Paul S de Vries; Nicholas L Smith; Maria Sabater-Lleal Journal: J Thromb Haemost Date: 2022-03-29 Impact factor: 16.036
Authors: John W Cole; Huichun Xu; Kathleen Ryan; Thomas Jaworek; Nicole Dueker; Patrick McArdle; Brady Gaynor; Yu-Ching Cheng; Jeffrey O'Connell; Steve Bevan; Rainer Malik; Naveed Uddin Ahmed; Philippe Amouyel; Sheraz Anjum; Joshua C Bis; David Crosslin; John Danesh; Stefan T Engelter; Myriam Fornage; Philippe Frossard; Christian Gieger; Anne-Katrin Giese; Caspar Grond-Ginsbach; Weang Kee Ho; Elizabeth Holliday; Jemma Hopewell; M Hussain; W Iqbal; S Jabeen; Jim Jannes; Ayeesha Kamal; Yoichiro Kamatani; Sandip Kanse; Manja Kloss; Mark Lathrop; Didier Leys; Arne Lindgren; W T Longstreth; Khalid Mahmood; Christa Meisinger; Tiina M Metso; Thomas Mosley; Martina Müller-Nurasyid; Bo Norrving; Eugenio Parati; Annette Peters; Alessandro Pezzini; I Quereshi; Asif Rasheed; A Rauf; T Salam; Jess Shen; Agnieszka Słowik; Tara Stanne; Konstantin Strauch; Turgut Tatlisumak; Vincent N Thijs; Steffen Tiedt; Matthew Traylor; Melanie Waldenberger; Matthew Walters; Wei Zhao; Giorgio Boncoraglio; Stéphanie Debette; Christina Jern; Christopher Levi; Hugh Markus; James Meschia; Arndt Rolfs; Peter Rothwell; Danish Saleheen; Sudha Seshadri; Pankaj Sharma; Cathie Sudlow; Bradford Worrall; O Colin Stine; Steven J Kittner; Braxton D Mitchell Journal: PLoS One Date: 2018-11-01 Impact factor: 3.240