Abstract 13651: Thrombomodulin Variants are Associated with Increased Mortality following CABG Surgery in Replicated Analyses
We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality following coronary artery bypass grafting (CABG).
Methods: Two separate cohorts of patients undergoing CABG 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. A panel of 96 SNPs in 52 candidate genes genotyped in the discovery cohort (N=1821) was tested in Cox proportional hazard models with incident death as endpoint. Variants with permutation- and covariate-adjusted p-values <0.05 and tagging SNPs in the respective candidate genes were tested in the validation cohort (N=936), with Bonferroni-adjusted p-values < 0.05 considered significant. In pooled analyses, we further investigated the ability of genetic variants to improve existing mortality prediction models (logistic EuroSCORE, and demographic and intraoperative covariates) by computing the net reclassification improvement (NRI) and integrated discrimination improvement (IDI).
Results: During follow-up, 196 deaths were observed. Two common variants of the thrombomodulin (THBD) gene (rs1042579, rs3176123) demonstrated significant independent associations with incident postoperative mortality in the two cohorts, respectively. The two variants are in complete linkage disequilibrium (r2=1.0). Covariate-adjusted survival for the combined cohort is illustrated in Fig 1. THBD genotype was highly significant in this model (p=1.63 × 10-5), with a hazard ratio (CI) of 2.78 (1.75, 4.42). The addition of THBD genotype resulted in an NRI of 0.385 (p=4.42×10-7) and an IDI of 0.019 (p=1.8×10-4).
Conclusions: Common allelic variants of the THBD gene may significantly contribute to increased long-term mortality risk following CABG. Addition of THBD genotype improves the classification ability of traditional postoperative mortality prediction models.
- © 2010 by American Heart Association, Inc.