Chromosome 9p21 Haplotypes and Prognosis in White and Black Patients With Coronary Artery Disease Yan Gong, PhD*; Amber L. Beitelshees, PharmD, MPH*; Rhonda M. Cooper-DeHoff, PharmD; Maximilian T. Lobmeyer, PhD; Taimour Y. Langaee, PhD; Jun Wu, MD; Sharon Cresci, MD; Michael A. Province, PhD; John A. Spertus, MD, MPH; Carl J. Pepine, MD; Julie A. Johnson, PharmD Background—Although numerous single-nucleotide polymorphisms (SNPs) in chromosome 9p21 have been associated with coronary artery disease (CAD) and incident myocardial infarction (MI) in whites, there are limited and conflicting reports on the association of this locus with prognosis in whites with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD. Methods and Results—We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertension patients with CAD of multiple races/ethnicities in INVEST-GENES (the International Verapamil SR Trandolapril Study Genetic Substudy) (n=1460 and n=5979 for 2 SNPs) with replication testing of 4 SNPs in the INFORM (Investigation of Outcomes From Acute Coronary Syndrome) study (n=714) of patients with acute coronary syndromes. In INVEST, the haplotype comprising the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in whites (odds ratio [OR], 0.72; 95% CI, 0.57 to 0.92; P=0.0085) but not in blacks (OR, 1.21; 95% CI, 0.68 to 1.24; P=0.52) or Hispanics (OR, 0.96; 95% CI, 0.65 to 1.44; P=0.86). A less commonly reported linkage disequilibrium block was associated with worse prognosis in INVEST in both whites (OR, 1.52; 95% CI, 1.20 to 1.93; P=0.0006) and blacks (OR, 4.11; 95% CI, 1.55 to 10.88; P=0.004). Conclusions—Our findings suggest that previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported linkage disequilibrium block warrants further investigation. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00133692. (Circ Cardiovasc Genet. 2011;4:169-178.) Key Words: chromosome 9p21  cardiovascular diseases  polymorphism, genetic  randomized controlled trial E pidemiological and experimental evidence indicate that coronary artery disease (CAD) arises from a combination of genetic and environmental factors. Four genome-wide association studies in 2007 independently identified the chromosomal locus 9p21 as being a susceptibility locus for CAD or myocardial infarction (MI) among whites. 1–4 Subse- quent studies have replicated these findings and found asso- ciation of this locus with also stroke and aortic aneurysm in Northern European and North American white popula- tions 1,5–9 and East Asian populations. 10,11 A recent meta-anal- ysis included 22 reports with 47 distinct data sets and found a statistically significant association between 9p21 SNPs and risk for coronary heart disease, CAD, or MI that varied by age at disease onset, with odds ratios (ORs) higher at younger ages (55 years) of disease onset. 12 The chromosome 9p21 represents the most replicated locus for CAD and MI in whites to date, with rs1333049 being the strongest single-nu- cleotide polymorphism (SNP), tagging multiple SNPs in high linkage disequilibrium (LD) in this region. The risk allele is common, with an allele frequency of almost 50%, and is Received July 9, 2010; accepted February 16, 2011. From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D., M.T.L., T.Y.L., J.A.J.), University of Florida College of Pharmacy, Gainesville, FL; Cardiovascular Division (A.L.B., S.C.), Department of Medicine, and Department of Genetics (J.W., M.A.P.), Division of Statistical Genomics, Washington University School of Medicine; St Louis, MO; Division of Cardiovascular Medicine (R.M.C.-D., C.J.P., J.A.J.), University of Florida College of Medicine, Gainesville, FL; and Mid America Heart Institute and University of Missouri (J.A.S.), Kansas City School of Medicine, Kansas City, MO. Dr Beitelshees is now at the University of Maryland School of Medicine, Division of Endocrinology, Diabetes and Nutrition, Baltimore, MD. Guest Editor for this article was Thomas P. Cappola, MD. *Drs Gong and Beitelshees contributed equally to this work. The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.110.959296/DC1. Correspondence to Julie A. Johnson, PharmD, Center for Pharmacogenomics, University of Florida, Health Science Center, PO Box 100486, Gainesville FL, 32610. E-mail johnson@cop.ufl.edu © 2011 American Heart Association, Inc. Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org DOI: 10.1161/CIRCGENETICS.110.959296 169 Downloaded from http://ahajournals.org by on May 31, 2020