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

Objective: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") 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. Methods: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele-specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, 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, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed 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 nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1-2.2). Conclusion: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group.