Gong Yan, Beitelshees Amber L, Cooper-DeHoff Rhonda M, Lobmeyer Maximilian T, Langaee Taimour Y, Wu Jun, Cresci Sharon, Province Michael A, Spertus John A, Pepine Carl J, Johnson Julie A
Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.
Circ Cardiovasc Genet. 2011 Apr;4(2):169-78. doi: 10.1161/CIRCGENETICS.110.959296. Epub 2011 Mar 3.
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.
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).
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.
尽管9号染色体短臂2区1带（9p21）上的众多单核苷酸多态性（SNP）已被证实与白人的冠状动脉疾病（CAD）及首次发生的心肌梗死（MI）相关，但关于该基因座与已患CAD白人患者预后的关联，相关报道有限且存在矛盾，而在黑人或西班牙裔人群中尚无此类报道。我们对“9p21多态性与有CAD记录的患者不良心血管结局风险增加相关”这一假说进行了研究。
我们在INVEST - GENES（国际维拉帕米缓释片群多普利研究基因子研究）中研究了155个9号染色体9p21 SNP与多种种族/族裔CAD高血压患者不良结局之间的关联（两个SNP分别有n = 1460和n = 5979例），并在急性冠脉综合征患者的INFORM（急性冠脉综合征结局研究）研究（n = 714例）中对4个SNP进行了重复检测。在INVEST研究中，包含广泛报道的9p21 SNP风险等位基因的单倍型与白人更好的预后相关（优势比[OR]，0.72；95%可信区间[CI]，0.57至0.92；P = 0.0085），但与黑人（OR，1.21；95% CI，0.68至1.24；P = 0.52）或西班牙裔（OR，0.96；95% CI，0.65至1.44；P = 0.86）无关。一个较少被报道的连锁不平衡区域与INVEST研究中白人（OR，1.52；95% CI，1.20至1.93；P = 0.0006）和黑人（OR，4.11；95% CI，1.55至10.88；P = 0.004）的较差预后相关。
我们的研究结果表明，先前报道的可预测CAD发生的9号染色体9p21 SNP与已患CAD患者不良结局的较高风险无关。较少被报道的连锁不平衡区域值得进一步研究。临床试验注册 - 网址：http://www.clinicaltrials.gov。唯一标识符：NCT00133692。
