COMT and ACE (Epi)genetic Variation Is Associated with Cognitive and Metabolic Resilience in Swiss Tactical Athletes

Resilience to stress integrates cognitive, physiological, and behavioral adaptations to sustain performance under adversity. Genetic variation in catechol-O-methyltransferase (<i>COMT</i>, rs4680) and angiotensin-converting enzyme (<i>ACE</i>, rs1799752) modulates dopaminergic and renin-angiotensin signaling, influencing tissue oxygenation and fatigue resistance. We examined <i>COMT</i>- and <i>ACE</i>-promoter methylation and genotypes in relation to resilience traits in Swiss tactical athletes (24.6 years) with a maximal power output of 534 W and 21,656 W, respectively, during cardiopulmonary exercise and elbow strike testing. At a 5% false-discovery rate, <i>COMT</i> genotype/methylation explained ~12% of the variance in cognitive performance and metabolic resilience, while <i>ACE</i> explained ~6-7% in strength-endurance and muscle resistance. Antidromic linear associations between <i>COMT</i> genotype and methylation with visual reaction time under reactive stress indicate opposing regulatory influences, best captured by regression models incorporating (epi)genetic covariates. The strongest methylation effects involved <i>COMT</i> promoter associations with muscle hemoglobin content across cardiopulmonary exercise zones (r = 0.43-0.58) and sport-specific strain (r = -0.46). <i>COMT</i>- and <i>ACE</i>-promoter methylation, correlated with time spent in the first aerobic training zone (r = 0.55 and 0.32), indicating environmentally responsive epigenetic modulation. These findings highlight neurovascular-metabolic coupling via dopaminergic and renin-angiotensin pathways as a key mechanism in stress adaptation. System-level adaptations in these pathways align with <i>COMT</i> and <i>ACE</i> (epi)genetic blood profiles, positioning them as candidate resilience biomarkers. Larger, preregistered studies with site-specific CpG analyses and mechanistic assays are needed to establish causal relevance and translational utility for resilience-informed performance optimization in high-stakes professionals.