The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype

Abstract

Objectives: Catechol-O-methyltransferase (COMT), a key enzyme in degrading stress hormones, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated “warriors”) withstand the onset of neuropsychiatric disorders and cognitive decline, while individuals with Met/Met and Val/Met genotypes (“non-warriors”) are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. Design: Prospective cohort. Setting: Two academic medical centers. Participants: 547 patients age ≥70 undergoing major non-cardiac surgery. Measurements: We collected blood, extracted DNA, and performed COMT genotyping using allele specific PCR assays, considering warriors vs. non-warriors. High plasma CRP, measured on postoperative day 2 (POD2) using ELISA, was defined by the highest sample-based quartile (≥234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, and surgery type, stratified by COMT genotype, to determine whether the association between CRP and delirium differs by COMT. Results: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk[RR] 1.0, 95% confidence interval[CI] 0.4–2.6). In contrast, among non-warriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1–2.2). Conclusions: COMT warriors may be protected against the increased risk of delirium associated with high POD2 CRP. With further confirmation, COMT genotype may help to target interventions for delirium prevention to the vulnerable non-warrior group.

Apolipoprotein E genotype and the association between C‐reactive protein and postoperative delirium: Importance of gene‐protein interactions

“…These findings (e.g., Ref. ) support the notion that delirium pathophysiology is complex and warrants examination beyond direct gene association studies. Separately, work in AD pathophysiology has uncovered complex biological mechanisms of AD by the identification of gene and protein networks contributing to an AD‐specific immune‐endocrine‐neuronal regulatory network .…”

“…Evidence for other indirect genetic influences has been observed in previous examinations of gene‐protein interactions with postoperative delirium. For instance, although no direct association between catechol‐O‐methyltransferase (COMT) genotype, a key regulator of the stress response, and postoperative delirium was observed, COMT genotype was found to modify the previously reported association between inflammatory marker C‐reactive protein (CRP) and postoperative delirium . Among older surgical patients with the COMT Val/Val genotype, high CRP measured on postoperative day 2 (POD2) was not associated with delirium.…”

“…For instance, although no direct association between catechol-O-methyltransferase (COMT) genotype, a key regulator of the stress response, and postoperative delirium was observed, COMT genotype was found to modify the previously reported association between inflammatory marker C-reactive protein (CRP) and postoperative delirium. 33 Among older surgical patients with the COMT Val/Val genotype, high CRP measured on postoperative day 2 (POD2) was not associated with delirium. In contrast, patients with COMT Val/Met or Met/Met genotypes and high POD2 CRP had an increased risk of postoperative delirium.…”

Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

“…Perturbations in executive function can result in delirium which affects mainly attention, and dementia which affects mainly memory. Although COMT does not appear to directly influence delirium, it modified the known association between C-reactive protein (CRP), an acute phase reactant, and postoperative delirium [34,35] Functional pain disorders A recent meta-analyses of COMT and functional pain disorders found that the low-activity met-allele was associated with fibromyalgia. An earlier meta-analysis also found that the met-allele was associated with fibromyalgia and widespread chronic pain, but not migraine headache or chronic musculoskeletal pain conditions [36,37] Chronic fatigue syndrome Chronic fatigue syndrome patients were more likely to be homozygous for the met-allele compared with val-allele carriers [38,39] Pain COMT low-activity haplotypes were associated with greater sensitivity to nociceptive, but lower sensitivity to neuropathic pain.…”

Systems Level Analysis and Identification of Pathways and Key Genes Associated with Delirium

“…These include direct and indirect effects of inflammatory, neuroendocrine, and gross anatomic or neurodegenerative mechanisms [ 7 ]. Moreover, candidate gene association studies on delirium have shown that apolipoprotein E [ 8 ], catechol-O-methyltransferase (COMT) [ 9 ], and dopamine-signaling genes such as dopamine receptor 2 [ 10 ] are related to the risk of delirium. Interleukin-related genes and the sodium/hydrogen exchanger gene were also identified as risk factors for delirium by a delirium-focused genome-wide association study (GWAS) [ 6 ].…”