Impact of Cytokine Gene Polymorphisms on Outcomes of Coronary Artery Bypass Graft Surgery

A potential source of complications after coronary artery bypass graft surgery (CABG) includes release of proinflammatory and anti-inflammatory cytokines like tumor necrosis factor (TNF)and interleukin (IL)-10, respectively. These are released secondary to ischemia-reperfusion injury, exposure of blood to bypass circuit, products of complement system, and/or endotoxin release from the GI tract. The G3 A transitions at 308 site within the promoter region of the TNFgene and 250 site within the first intron of the TNFgene is associated with elevated levels of TNF. Similarly, the G3 A transition at 1082 site within the promoter region of the IL-10 gene is associated with lower IL-10 levels. We hypothesize that polymorphisms within these genes will be associated with variable outcomes after CABG. This was a prospective observational study. Patients were weaned by a standardized respiratory protocol and assessed at 8 h, 24 h, and 48 h for failure to wean. Precollected blood was used for gene analysis using polymerase chain reaction and restriction enzyme digestion (for TNF sites) or heteroduplex generation (IL-10 sites) as described previously. The primary end points were duration of mechanical ventilation and need for transfusion of blood products after surgery. The secondary end point was 30-day mortality. To explore the potential role of preoperative genotyping, we examined the role of a scoring system based on preoperative risk factors (SS) by Spivack et al1 and TNF haplotype to predict risk of prolonged mechanical ventilation (PMV). Three hundred fifty-five patients (262 patients undergoing conventional CABG) were enrolled. Patients with TNF 250G/-308G (TNF-GG) haplotype had longer duration of mechanical ventilation compared to those without this haplotype (30.3 h vs 12.7 h, p 0.006). Patients with the TNF-GG haplotype were less likely to be extubated at 48 h (8.5% vs 2%, p 0.006). This association of the TNF-GG haplotype was independent of preoperative risk factors. The TNF haplotypes had no effect on bleeding complications and mortality after CABG. The TNF-GG haplotype was associated with PMV in patients undergoing conventional CABG only (34.8 h vs 17.5 h, p 0.006) with no effect on patients undergoing off-pump CABG (OPCAB) [13.2 h vs 10.8 h, p not significant]. Using Bayesian analysis and pretest probability of 6.5%, patients with SS 0 (n 121) had a posttest probability of 1.4% (low risk). In patients with SS 0 (n 141), posttest probability was 10.7%. Gene analysis of patients with SS 0 resulted in posttest probability of 3.5% (low risk) for AA genotype (n 59) and 16.1% (high risk) for non-AA genotypes (n 82). Risk of PMV for patients undergoing OPCAB (n 93) was 3.2% regardless of genotypes or SS. The IL-10 polymorphisms had no effect on either of the primary end points. The G allele was associated with a higher mortality rate compared to A allele (7.4% vs 2.7%, p 0.05). In conclusion, the 250G/-308G haplotype is associated with PMV and the GG genotype at 1082 site is associated with higher mortality after CABG. SS and TNF haplotype may be used in combination to predict risk of PMV after CABG. Low-risk patients may proceed to surgery. In high-risk patients, OPCAB may be performed to reduce risk of PMV.