Chromosome 9p21 Variant Predicts Mortality After Coronary Artery Bypass Graft Surgery

Background— Recent genome-wide association studies have identified several chromosome 9p21 single nucleotide polymorphisms associated with coronary artery disease and myocardial infarction in nonsurgical populations. We have recently demonstrated an independent association between these 9p21 variants and perioperative myocardial injury after isolated primary coronary artery bypass graft (CABG) surgery. This study investigated the association of a 9p21 variant with mortality in patients after CABG surgery and its prognostic value to improve the EuroSCORE. Methods and Results— In a 2-center, prospective, observational study of 846 white primary CABG surgery patients, we genotyped rs10116277, the 9p21 variant with the strongest association to perioperative myocardial injury in our cohort. To estimate the utility of rs10116277 for predicting all-cause mortality within 5 years after surgery, a Cox proportional hazard model was constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) while adjusting for demographics and clinical covariates. The homozygote minor allele of rs10116277 was associated with significantly increased risk of all-cause mortality even after adjusting for other clinical predictors of mortality in a Cox proportional hazards model (HR, 1.7; 95% CI, 1.1–2.7; P=0.026). Addition of rs10116277 to the logistic EuroSCORE also significantly improved model prediction for mortality (HR, 1.82; 95% CI, 1.15–2.88; P=0.01). Conclusion— The 9p21 variant rs10116277 is independently associated with all-cause mortality after primary CABG surgery in whites and significantly improves the predictive value of the logistic EuroSCORE. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00281164.

[1]  Kuang-Yu Liu,et al.  Common genetic variants on chromosome 9p21 predict perioperative myocardial injury after coronary artery bypass graft surgery. , 2010, The Journal of thoracic and cardiovascular surgery.

[2]  M. Ruel,et al.  Statins and coronary artery bypass graft surgery: preoperative and postoperative efficacy and safety , 2009, Expert opinion on drug safety.

[3]  S. Aranki,et al.  Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting. , 2009, European heart journal.

[4]  E. Boerwinkle,et al.  Impact of Adding a Single Allele in the 9p21 Locus to Traditional Risk Factors on Reclassification of Coronary Heart Disease Risk and Implications for Lipid-Modifying Therapy in the Atherosclerosis Risk in Communities Study , 2009, Circulation. Cardiovascular genetics.

[5]  Karen L. Mohlke,et al.  INK4/ARF Transcript Expression Is Associated with Chromosome 9p21 Variants Linked to Atherosclerosis , 2009, PloS one.

[6]  Joshua M. Korn,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[7]  Nancy R Cook,et al.  Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3 , 2009, Annals of Internal Medicine.

[8]  Florian Kronenberg,et al.  Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. , 2008, Journal of the American College of Cardiology.

[9]  B. Klanke,et al.  Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16INK4a , 2008, Hypertension.

[10]  Stefan Lorkowski,et al.  Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. , 2008, Human molecular genetics.

[11]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[12]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[13]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[14]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[15]  David M Herrington,et al.  Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group , 2007, Circulation.

[16]  D. Mark,et al.  Myocardial infarction following coronary artery bypass graft surgery increases healthcare resource utilization , 2007, Critical care medicine.

[17]  H. Bloomfield,et al.  Prognostic significance of elevated cardiac troponin I after heart surgery. , 2007, The Annals of thoracic surgery.

[18]  I. Bièche,et al.  Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. , 2007, Cancer research.

[19]  Jonathan C. Cohen,et al.  A Common Allele on Chromosome 9 Associated with Coronary Heart Disease , 2007, Science.

[20]  N. Sharpless,et al.  The Regulation of INK4/ARF in Cancer and Aging , 2006, Cell.

[21]  G. Hillis,et al.  Relationship Between Postoperative Cardiac Troponin I Levels and Outcome of Cardiac Surgery , 2006, Circulation.

[22]  F. Harrell,et al.  Prognostic/Clinical Prediction Models: Multivariable Prognostic Models: Issues in Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors , 2005 .

[23]  H. Priebe.  Perioperative myocardial infarction--aetiology and prevention. , 2005, British journal of anaesthesia.

[24]  S. Yusuf,et al.  Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study , 2004, The Lancet.

[25]  S. Nashef,et al.  The logistic EuroSCORE , 2003 .

[26]  J. Raffetto,et al.  Synopsis on cellular senescence and apoptosis. , 2001, Journal of vascular surgery.

[27]  R. Fitzgerald,et al.  Usefulness of cardiac troponin I in patients undergoing open heart surgery. , 2001, American heart journal.

[28]  J. W. Schaeffer,et al.  ACC/AHA guidelines for the management of patients with unstable angina and non–st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) , 2000 .

[29]  Anthony C. Davison,et al.  Bootstrap Methods and Their Application , 1998 .

[30]  B. Klanke,et al.  Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p 16 INK 4 a , 2008 .

[31]  J. W. Schaeffer,et al.  ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). , 2000, Journal of the American College of Cardiology.

[32]  ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. , 2000, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.