BACKGROUND: We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality after coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: Two separate cohorts of patients undergoing CABG surgery at a single institution were examined, and all-cause mortality between 30 days and 5 years after the index CABG was ascertained from the National Death Index. In a discovery cohort of 1018 patients, a panel of 90 single-nucleotide polymorphisms (SNPs) in 49 candidate genes was tested with Cox proportional hazard models to identify clinical and genomic multivariate predictors of incident death. After adjustment for multiple comparisons and clinical predictors of mortality, the homozygote minor allele of a common variant in the thrombomodulin (THBD) gene (rs1042579) was independently associated with significantly increased risk of all-cause mortality (hazard ratio, 2.26; 95% CI, 1.31 to 3.92; P=0.003). Six tag SNPs in the THBD gene, 1 of which (rs3176123) in complete linkage disequilibrium with rs1042579, were then assessed in an independent validation cohort of 930 patients. After multivariate adjustment for the clinical predictors identified in the discovery cohort and multiple testing, the homozygote minor allele of rs3176123 independently predicted all-cause mortality (hazard ratio, 3.6; 95% CI, 1.67 to 7.78; P=0.001). CONCLUSIONS: In 2 independent cardiac surgery cohorts, linked common allelic variants in the THBD gene are independently associated with increased long-term mortality risk after CABG and significantly improve the classification ability of traditional postoperative mortality prediction models.
BACKGROUND: We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality after coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: Two separate cohorts of patients undergoing CABG surgery at a single institution were examined, and all-cause mortality between 30 days and 5 years after the index CABG was ascertained from the National Death Index. In a discovery cohort of 1018 patients, a panel of 90 single-nucleotide polymorphisms (SNPs) in 49 candidate genes was tested with Cox proportional hazard models to identify clinical and genomic multivariate predictors of incident death. After adjustment for multiple comparisons and clinical predictors of mortality, the homozygote minor allele of a common variant in the thrombomodulin (THBD) gene (rs1042579) was independently associated with significantly increased risk of all-cause mortality (hazard ratio, 2.26; 95% CI, 1.31 to 3.92; P=0.003). Six tag SNPs in the THBD gene, 1 of which (rs3176123) in complete linkage disequilibrium with rs1042579, were then assessed in an independent validation cohort of 930 patients. After multivariate adjustment for the clinical predictors identified in the discovery cohort and multiple testing, the homozygote minor allele of rs3176123 independently predicted all-cause mortality (hazard ratio, 3.6; 95% CI, 1.67 to 7.78; P=0.001). CONCLUSIONS: In 2 independent cardiac surgery cohorts, linked common allelic variants in the THBD gene are independently associated with increased long-term mortality risk after CABG and significantly improve the classification ability of traditional postoperative mortality prediction models.
Authors: Samer A M Nashef; Francois Roques; Bradley G Hammill; Eric D Peterson; Philippe Michel; Frederick L Grover; Richard K H Wyse; T Bruce Ferguson Journal: Eur J Cardiothorac Surg Date: 2002-07 Impact factor: 4.191
Authors: Jochen D Muehlschlegel; Kuang-Yu Liu; Tjörvi E Perry; Amanda A Fox; Charles D Collard; Stanton K Shernan; Simon C Body Journal: Circulation Date: 2010-09-14 Impact factor: 29.690
Authors: Marc Ruel; Cesario Bianchi; Tanveer A Khan; Shu Xu; John R Liddicoat; Pierre Voisine; Eugenio Araujo; Helen Lyon; Isaac S Kohane; Towia A Libermann; Frank W Sellke Journal: J Thorac Cardiovasc Surg Date: 2003-11 Impact factor: 5.209
Authors: Henry Völzke; Julia Engel; Volker Kleine; Christian Schwahn; Johannes B Dahm; Lothar Eckel; Rainer Rettig Journal: Chest Date: 2002-07 Impact factor: 9.410
Authors: P E Morange; C Simon; M C Alessi; G Luc; D Arveiler; J Ferrieres; P Amouyel; A Evans; P Ducimetiere; I Juhan-Vague Journal: Circulation Date: 2004-03-15 Impact factor: 29.690
Authors: Amy Moore; Daniel A Enquobahrie; Sixto E Sanchez; Cande V Ananth; Percy N Pacora; Michelle A Williams Journal: Int J Mol Epidemiol Genet Date: 2012-11-15
Authors: Mihai V Podgoreanu; Joseph P Mathew; Miklos D Kertai; Yen-Wei Li; Yi-Ju Li; Svati H Shah; William E Kraus; Manuel L Fontes; Mark Stafford-Smith; Mark F Newman Journal: Circ Cardiovasc Genet Date: 2014-07-21
Authors: Miklos D Kertai; Yunqi Ji; Yi-Ju Li; Joseph P Mathew; James P Daubert; Mihai V Podgoreanu Journal: Can J Anaesth Date: 2016-02-08 Impact factor: 5.063
Authors: Miklos D Kertai; Shan Zhou; Jörn A Karhausen; Mary Cooter; Edmund Jooste; Yi-Ju Li; William D White; Solomon Aronson; Mihai V Podgoreanu; Jeffrey Gaca; Ian J Welsby; Jerrold H Levy; Mark Stafford-Smith; Joseph P Mathew; Manuel L Fontes Journal: Anesthesiology Date: 2016-02 Impact factor: 7.892
Authors: Matthias Kornek; Marcus-André Deutsch; Stefan Eichhorn; Harald Lahm; Stefan Wagenpfeil; Markus Krane; Ruediger Lange; Johannes Boehm Journal: Dis Markers Date: 2013-08-07 Impact factor: 3.434