Abstract 4777: Variants in CDKN9 associated with Perioperative Myocardial Injury after Cardiac Surgery
Coronary artery disease is the leading cause of death worldwide. Nearly one million people annually suffer perioperative myocardial injury (PMI) during or after surgery. A recent genome wide association study identified an association between MI in non-surgical populations and common genetic variants on chromosome 9p21, adjacent to genes for the cyclin-dependent kinases CDKN2A/B. We hypothesized that these variants are also responsible for PMI after isolated primary CABG surgery. In a prospective observational study of 877 Caucasian CABG patients at 2 US centers, we genotyped 61 haplotype-tagging SNPs, covering 436 kbp of the CDKN2A and CDKN2B genic region. A multivariable logistic model was used to adjust for previously identified clinical covariates of PMI including severity of coronary disease. Multiple testing of SNPs was corrected for with family-wise (FW) errors. After CABG, 10% of patients developed PMI defined as a peak postoperative cTnI greater 8.25 mcg/L. Among the 61 SNPs examined, rs10116277 (G) and rs6475606 (C) describe a single haplotype that is significantly associated with PMI, after accounting for clinical covariates (additive model OR=1.7, 95% CI 1.3– 2.4, asymptotic P=5.7×10−4, FW empirical P=0.039). The two SNPs are 87 and 72 kbp 5′ of CDKN2A and CDKN2B, respectively. The GC haplotype frequencies for the overall cohort, cases and controls are 41%, 53% and 40%, respectively. Levels of postoperative cTnI were incrementally increased for each additional copy of the GC haplotype (Figure 1⇓). In conclusion, we have identified common genetic variants in 9p21 associated with PMI. The functional mechanisms remain to be elucidated.