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
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    • "The other CRP variant associated with CHD is rs1130864, where the change of cytosine to thymine at position 1444 has taken place [12] [13] [14]. With regard to polymorphisms rs2794521 and rs1205, these have been less studied in association studies with CHD, but similarly to the above mentioned polymorphisms they have yielded interesting outcomes [14] [15] [16]. The genetic change of rs2794521 occurs at position 717, where a cytosine is replaced by thymine; as for rs1205 a guanine is substituted by adenine at position 3872 [11] [17]. "
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    ABSTRACT: It is widely acknowledged that cardiovascular heart disease (CHD) has a genetic influence. Several studies have investigated the role of inflammatory markers like C-reactive protein (CRP) and tumor necrosis factor α (TNF-α) in the causation of cardiovascular diseases. Although there have been several positive studies associating CRP and TNF-α genes with CHD, the evidence is not entirely consistent. Therefore, we performed a meta-analysis to gain a better understanding into this issue. The meta-analysis was conducted with 22 articles of genetic association studies of CRP (G1059C rs1800947, C1444T rs1130864, C717T rs2794521 and G3872A rs1205) and TNF-α (C857T rs1799724, C863A rs1800630 and T1031C rs1799964) genes. To analyze the association of these variants with CHD we used the following models: allelic, additive, dominant and recessive. In addition, we performed a sub-group analysis by Caucasian population using the same four models. CRP and TNF-α gene polymorphisms showed a positive significant association with CHD. This study provides evidence that rs2794521 of the CRP gene and rs1799724, rs1800630 and rs1799964 of the TNF-α gene polymorphisms may be risk factors to manifest CHD. The analysis of rs1800947 and rs1205 of the CRP gene yielded a protective effect in the pathogenesis of this disease. Only the analysis of the rs1130864 polymorphism showed a lack of association with CHD. To have conclusive outcomes it is necessary to integrate more studies to confirm our findings.
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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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    • "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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