Lu-Chen Weng1, Weihong Tang2, Stephen S Rich3, Nicholas L Smith4, Susan Redline5, Christopher J O'Donnell6, Saonli Basu7, Alexander P Reiner8, Joseph A Delaney8, Russell P Tracy9, Cameron D Palmer10, Taylor Young10, Qiong Yang11, Aaron R Folsom1, Mary Cushman12. 1. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. 2. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. Electronic address: tang0097@umn.edu. 3. Department of Public Health Sciences and the Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. 4. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA. 5. Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 6. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. 7. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA. 8. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. 9. Departments of Pathology and Biochemistry, University of Vermont, Burlington, VT, USA. 10. Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. 11. The NHLBI's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA. 12. Departments of Medicine and Pathology, University of Vermont, Burlington, VT, USA.
Abstract
INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations. MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis. RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer. CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.
INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations. MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis. RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer. CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGArs6050 in AAs and the factor V Leiden variant in Hispanics.
Authors: Christina L Wassel; Leslie A Lange; Brendan J Keating; Kira C Taylor; Andrew D Johnson; Cameron Palmer; Lindsey A Ho; Nicholas L Smith; Ethan M Lange; Yun Li; Qiong Yang; Joseph A Delaney; Weihong Tang; Geoffrey Tofler; Susan Redline; Herman A Taylor; James G Wilson; Russell P Tracy; David R Jacobs; Aaron R Folsom; David Green; Christopher J O'Donnell; Alexander P Reiner Journal: Blood Date: 2010-10-26 Impact factor: 22.113
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: J Voorberg; J Roelse; R Koopman; H Büller; F Berends; J W ten Cate; K Mertens; J A van Mourik Journal: Lancet Date: 1994-06-18 Impact factor: 79.321
Authors: Kiran Musunuru; Guillaume Lettre; Taylor Young; Deborah N Farlow; James P Pirruccello; Kenechi G Ejebe; Brendan J Keating; Qiong Yang; Ming-Huei Chen; Nina Lapchyk; Andrew Crenshaw; Liuda Ziaugra; Anthony Rachupka; Emelia J Benjamin; L Adrienne Cupples; Myriam Fornage; Ervin R Fox; Susan R Heckbert; Joel N Hirschhorn; Christopher Newton-Cheh; Marcia M Nizzari; Dina N Paltoo; George J Papanicolaou; Sanjay R Patel; Bruce M Psaty; Daniel J Rader; Susan Redline; Stephen S Rich; Jerome I Rotter; Herman A Taylor; Russell P Tracy; Ramachandran S Vasan; James G Wilson; Sekar Kathiresan; Richard R Fabsitz; Eric Boerwinkle; Stacey B Gabriel Journal: Circ Cardiovasc Genet Date: 2010-04-17
Authors: P L Lutsey; M Cushman; L M Steffen; D Green; R G Barr; D Herrington; P Ouyang; A R Folsom Journal: J Thromb Haemost Date: 2006-09-26 Impact factor: 5.824
Authors: Roland von Känel; Joel E Dimsdale; Sonia Ancoli-Israel; Paul J Mills; Thomas L Patterson; Christine L McKibbin; Christopher Archuleta; Igor Grant Journal: J Am Geriatr Soc Date: 2006-03 Impact factor: 5.562
Authors: Mary Cushman; Aaron R Folsom; Lu Wang; Nena Aleksic; Wayne D Rosamond; Russell P Tracy; Susan R Heckbert Journal: Blood Date: 2002-09-26 Impact factor: 22.113
Authors: Laura M Raffield; Neil A Zakai; Qing Duan; Cecelia Laurie; Joshua D Smith; Marguerite R Irvin; Margaret F Doyle; Rakhi P Naik; Ci Song; Ani W Manichaikul; Yongmei Liu; Peter Durda; Jerome I Rotter; Nancy S Jenny; Stephen S Rich; James G Wilson; Andrew D Johnson; Adolfo Correa; Yun Li; Deborah A Nickerson; Kenneth Rice; Ethan M Lange; Mary Cushman; Leslie A Lange; Alex P Reiner Journal: Arterioscler Thromb Vasc Biol Date: 2017-09-14 Impact factor: 8.311
Authors: Charles F Hayfron-Benjamin; Charlotte Mosterd; Anke H Maitland-van der Zee; Daniel H van Raalte; Albert G B Amoah; Charles Agyemang; Bert-Jan van den Born Journal: EClinicalMedicine Date: 2021-07-07