Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.
BACKGROUND
The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery.


RESULTS
We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703).


CONCLUSIONS
Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.
Podgoreanu
M V
MV
Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710, USA. mihai.podgoreanu@duke.edu
White
W D
WD
Morris
R W
RW
Mathew
J P
JP
Stafford-Smith
M
M
Welsby
I J
IJ
Grocott
H P
HP
Milano
C A
CA
Newman
M F
MF
Schwinn
D A
DA
D000368:Aged; D000483:Alleles; D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D015331:Cohort Studies; D019040:E-Selectin / Q000235:genetics; D017558:Elective Surgical Procedures; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000453:epidemiology*; D011446:Prospective Studies; D012372:ROC Curve; D012306:Risk; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000235:genetics*
D019040:E-Selectin; D015850:Interleukin-6; D018799:Intercellular Adhesion Molecule-1