title: Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses.
abstract: 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.
  
  
  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.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Lobato
authors.forename: William D
authors.initials: WD
authors.lastname: White
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mathew
authors.forename: Mark F
authors.initials: MF
authors.lastname: Newman
authors.forename: Peter K
authors.initials: PK
authors.lastname: Smith
authors.forename: Charles B
authors.initials: CB
authors.lastname: McCants
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.forename: Mihai V
authors.initials: MV
authors.lastname: Podgoreanu
mesh_terms: D000368:Aged; D015331:Cohort Studies; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000401:mortality* / Q000601:surgery*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D018180:Thrombomodulin / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D018180:Thrombomodulin