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CLINICAL RESEARCH: CARDIAC SURGERY

Genetic Variants in P-Selectin and C-Reactive Protein Influence Susceptibility to Cognitive Decline After Cardiac Surgery

Joseph P. Mathew, MD^_*,_*, Mihai V. Podgoreanu, MD^_*, Hilary P. Grocott, MD^_*, William D. White, MPH^_*, Richard W. Morris, PhD^_*, Mark Stafford-Smith, MD^_*, G. Burkhard Mackensen, MD^_*, Christine S. Rinder, MD^||, James A. Blumenthal, PhD, Debra A. Schwinn, MD^_*,,, Mark F. Newman, MD^_* for the PEGASUS Investigative Team

^_* Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina
Department of Pharmacology/Cancer Biology, Duke University Medical Center, Durham, North Carolina
Duke Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
^|| Departments of Anesthesiology and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut.

Manuscript received August 25, 2006; revised manuscript received December 6, 2006, accepted January 9, 2007.

^_* Reprint requests and correspondence: Dr. Joseph P. Mathew, Box 3094, Duke University Medical Center, Durham, North Carolina 27710. (Email: mathe014{at}mc.duke.edu).

Objectives: We hypothesized that candidate gene polymorphisms in biologic pathways regulating inflammation, cell matrix adhesion/interaction, coagulation-thrombosis, lipid metabolism, and vascular reactivity are associated with postoperative cognitive deficit (POCD).

Background: Cognitive decline is a common complication of coronary artery bypass graft (CABG) surgery and is associated with a reduced quality of life.

Methods: In a prospective cohort study of 513 patients (86% European American) undergoing CABG surgery with cardiopulmonary bypass, a panel of 37 single-nucleotide polymorphisms (SNPs) was genotyped by mass spectrometry. Association between these SNPs and cognitive deficit at 6 weeks after surgery was tested using multiple logistic regression accounting for age, level of education, baseline cognition, and population structure. Permutation analysis was used to account for multiple testing.

Results: We found that minor alleles of the CRP 1059G/C SNP (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.16 to 0.78; p = 0.013) and the SELP 1087G/A SNP (OR 0.51, 95% CI 0.30 to 0.85; p = 0.011) were associated with a reduction in cognitive deficit in European Americans (n = 443). The absolute risk reduction in the observed incidence of POCD was 20.6% for carriers of the CRP 1059C allele and 15.2% for carriers of the SELP 1087A allele. Perioperative serum C-reactive protein (CRP) and degree of platelet activation were also significantly lower in patients with a copy of the minor alleles, providing biologic support for the observed allelic association.

Conclusions: The results suggest a contribution of P-selectin and CRP genes in modulating susceptibility to cognitive decline after cardiac surgery, with potential implications for identifying populations at risk who might benefit from targeted perioperative antiinflammatory strategies.

Abbreviations and Acronyms   AA = African American   CABG = coronary artery bypass graft   CD62P = P-selectin   CPB = cardiopulmonary bypass   CRP = C-reactive protein   EA = European American   NA = Native American   POCD = postoperative cognitive deficit   SELP = P-selectin gene   SNP = single-nucleotide polymorphism

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