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

Department of Anesthesiology, Duke University, Durham, North Carolina, United States
Journal of the American College of Cardiology (Impact Factor: 16.5). 06/2007; 49(19):1934-42. DOI: 10.1016/j.jacc.2007.01.080
Source: PubMed


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

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Available from: Mihai Podgoreanu, Oct 07, 2015
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    • "An individual preoperative risk assessment could offer crucial information to clinicians and finally lead to improved outcomes. The emergence of perioperative genomics has enabled the detection of potential genetic risk factors in order to individualize and optimize therapy [3–7]. "
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    ABSTRACT: Background. Cardiac surgery-associated acute kidney injury (CSA-AKI) depicts a major complication after cardiac surgery using cardiopulmonary bypass (CPB). Objective. CSA-AKI has clearly been linked to increased perioperative morbidity and mortality. Dysregulations of vasomotor tone are assumed to be causal for CSA-AKI. While catechol-O-methyltransferase (COMT) is involved in metabolizing catecholamines, a single-nucleotide polymorphism (SNP) in the COMT gene leads to different enzyme activities according to genotype. Pilot studies found associations between those COMT genotypes and CSA-AKI. Methods. We prospectively included 1741 patients undergoing elective cardiac surgery using cardiopulmonary bypass (CPB). Patients were genotyped for COMT-Val158Met-(G/A) polymorphism (rs4680). Results. Demographic characteristics and procedural data revealed no significant differences between genotypes. No association between COMT genotypes and the RIFLE criteria could be detected. A multiple linear regression analysis for postoperative creatinine increase revealed highly significant associations for aortic cross-clamp time (P < 0.001), CPB time (P < 0.001), norepinephrine (P < 0.001), and age (P < 0.001). No associations were found for COMT genotypes or baseline creatinine. With an R (2) = 0.39 and a sample size of 1741, the observed power of the regression analysis was >99%. Conclusions. Based on our results, we can rule out an association between the COMT-Val158Met-(G/A) polymorphism and the appearance of CSA-AKI.
    Disease markers 08/2013; 35(2):129-34. DOI:10.1155/2013/279046 · 1.56 Impact Factor
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    • "However, it is similar to the prospective predictive power (∼5%) of the serum P-selectin levels on the intersubject variability in the carotid intima–media thickness measured 5 years later. Our findings also support the hypothesis of a direct genetic relationship between P-selectin expression and cerebral atrophy as proposed by two studies that demonstrated neurocognitive differences in the elderly carriers of 1087 allele of this gene (Mathew et al., 2007; Gunstad et al., 2009). However, allele-specific PCR validation will be necessary to name the specific genetic variants that are responsible for this association. "
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    ABSTRACT: Background and Purpose: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity. Methods: The subject pool consisted of 369 (219F; aged 28-85, average = 47.1 ± 12.7 years) normally aging, community-dwelling members of large extended Mexican-American families. Genetic correlation analysis decomposed phenotypic correlation coefficients into genetic and environmental components among 13 leukocyte-based mRNA gene expressions and three whole-brain and regional measurements of cerebral integrity: cortical gray matter thickness, fractional anisotropy of cerebral white matter, and the volume of hyperintensive WM lesions. Results: From the 13 gene expressions, significant phenotypic correlations were only found for the P- and L-selectin expression levels. Increases in P-selectin expression levels tracked with decline in cerebral integrity while the opposite trend was observed for L-selectin expression. The correlations for the P-selectin expression were driven by shared genetic factors, while the correlations with L-selectin expression were due to shared environmental effects. Conclusion: This study demonstrated that P-selectin expression shared a significant variance with measurements of cerebral integrity and posits elevated P-selectin expression levels as a potential risk factor of hypertension-related cerebral atrophy.
    Frontiers in Genetics 05/2012; 3:65. DOI:10.3389/fgene.2012.00065
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    • "3. Inflammation, activated during CPB, has been identified as a risk factor of POCD [23]. Specific proinflammatory genetic polymorphisms including CRP and IL-6 polymorphisms are associated with POCD, thus possibly explaining the variable susceptibility to POCD [24]. "
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    ABSTRACT: Neurologic deficits after cardiac surgery are common complications. Aim of this prospective observational pilot study was to investigate the incidence of postoperative cognitive deficit (POCD) after cardiac surgery, provided that relevant decrease of cerebral oxygen saturation (cSO2) is avoided during cardiopulmonary bypass. cSO2 was measured by near infrared spectroscopy in 35 patients during cardiopulmonary bypass. cSO2 was kept above 80% of baseline and above 55% during anesthesia including cardiopulmonary bypass. POCD was tested by trail making test, digit symbol substitution test, Ray's auditorial verbal learning test, digit span test and verbal fluency test the day before and 5 days after surgery. POCD was defined as a decline in test performance that exceeded - 20% from baseline in two tests or more. Correlation of POCD with lowest cSO2 and cSO2 - threshold were determined explorative. POCD was observed in 43% of patients. Lowest cSO2 during cardiopulmonary bypass was significantly correlated with POCD (p = 0.015, r2 = 0.44, without Bonferroni correction). A threshold of 65% for cSO2 was able to predict POCD with a sensitivity of 86.7% and a specificity of 65.0% (p = 0.03, without Bonferroni correction). Despite a relevant decrease of cerebral oxygen saturation was avoided in our pilot study during cardiopulmonary bypass, incidence of POCD was comparable to that reported in patients without monitoring. A higher threshold for cSO2 may be needed to reduce the incidence of POCD.
    BMC Anesthesiology 03/2011; 11(1):7. DOI:10.1186/1471-2253-11-7 · 1.38 Impact Factor
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