Thrombomodulin Gene Variants Are Associated With Increased Mortality After Coronary Artery Bypass Surgery in Replicated Analyses

Robert L. Lobato, MD, MS;
William D. White, MPH;
Joseph P. Mathew, MD;
Mark F. Newman, MD;
Peter K. Smith, MD;
Charles B. McCants, BS;
John H. Alexander, MD, MHSc;
Mihai V. Podgoreanu, MD;
for the Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team

+ Author Affiliations

From the Department of Anesthesia (R.L.L.), Stanford University School of Medicine, Stanford, CA; and Department of Anesthesiology (R.L.L., W.D.W., J.P.M., M.F.N., M.V.P.), Department of Surgery (P.K.S.), Department of Medicine (J.H.A.), Duke University Medical Center, and Duke Clinical Research Institute (M.F.N., C.B.M., J.H.A., M.V.P.), Durham, NC.

Correspondence to Mihai V. Podgoreanu, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. E-mail mihai.podgoreanu@duke.edu

Presented at the 2010 American Heart Association meeting in Chicago, IL, November 12–16, 2010.

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.

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.

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