Published Online
on July 28, 2005

A more recent version of this article appeared on September 1, 2005

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Submitted on February 16, 2005
Revised on April 18, 2005
Accepted on April 21, 2005

Genetic Polymorphisms and the Risk of Stroke After Cardiac Surgery

Hilary P. Grocott MD, FRCPC^*; William D. White MPH; Richard W. Morris PhD; Mihai V. Podgoreanu MD; Joseph P. Mathew MD; Dahlia M. Nielsen PhD; Debra A. Schwinn MD; Mark F. Newman MD; for the Perioperative Genetics and Safety Outcomes Study (PEGASUS) Investigative Team

From the Departments of Anesthesiology (H.P.G., W.D.W., R.W.M., M.P., J.P.M., D.A.S., M.F.N.) and Pharmacology/Cancer Biology (D.A.S.), Duke University Medical Center, Durham, NC; and the Department of Statistics (D.M.N.), North Carolina State University, Raleigh.

^* To whom correspondence should be addressed. E-mail: h.grocott{at}duke.edu.

Background and Purpose--Stroke represents a significant cause of morbidity and mortality after cardiac surgery. Although the risk of stroke varies according to both patient and procedural factors, the impact of genetic variants on stroke risk is not well understood. Therefore, we tested the hypothesis that specific genetic polymorphisms are associated with an increased risk of stroke after cardiac surgery.

Methods--Patients undergoing cardiac surgery utilizing cardiopulmonary bypass surgery were studied. DNA was isolated from preoperative blood and analyzed for 26 different single-nucleotide polymorphisms. Multivariable logistic regression modeling was used to determine the association of clinical and genetic characteristics with stroke. Permutation analysis was used to adjust for multiple comparisons inherent in genetic association studies.

Results--A total of 1635 patients experiencing 28 strokes (1.7%) were included in the final genetic model. The combination of the 2 minor alleles of C-reactive protein (CRP; 3'UTR 1846C/T) and interleukin-6 (IL-6; -174G/C) polymorphisms, occurring in 583 (35.7%) patients, was significantly associated with stroke (odds ratio, 3.3; 95% CI, 1.4 to 8.1; P=0.0023). In a multivariable logistic model adjusting for age, the CRP and IL-6 single-nucleotide polymorphism combination remained significantly associated with stroke (P=0.0020).

Conclusions--We demonstrate that common genetic variants of CRP (3'UTR 1846C/T) and IL-6 (-174G/C) are significantly associated with the risk of stroke after cardiac surgery, suggesting a pivotal role of inflammation in post-cardiac surgery stroke.

Key words: cardiac surgical procedures • C-reactive protein • interleukin-6 • polymorphism • stroke

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