Association Between CTSG Variants and Persistent Postoperative Pain After Cardiac Surgery

BACKGROUND: Cathepsin G (CTSG) is a neutrophil-derived serine protease implicated in inflammatory pain modulation. Genetic variation in CTSG may influence postoperative pain susceptibility. This study evaluated the association between CTSG polymorphisms, CTSG plasma concentration and enzymatic activity, and long-term pain after cardiac surgery. METHODS: We conducted a prospective cohort study including 255 Caucasian adults undergoing elective cardiac surgery via median sternotomy. CTSG single nucleotide polymorphisms (SNPs) rs2070697, rs2236742, and rs45567233 were genotyped. A random subsample of 107 patients underwent measurement of CTSG plasma concentration and enzymatic activity. Pain intensity (visual analogue scale VAS) at rest and with movement was assessed at 24 hours, 1 month, 6 months, and 12 months. Ordinal logistic regression was used to analyze associations between CTSG variants and pain. Mendelian randomization evaluated the causal effect of CTSG activity on pain. RESULTS: Overall, 16/250 patients (6.4%) reported moderate to severe postsurgical pain during movement at 6 months, and 6/178 patients (3.3%) at 12 months. At 1 month, pain was associated with higher BMI ( P = .016); at 12 months, it was more frequent in women ( P < .001) and in patients using antidepressants ( P = .022). The rs2070697 AA genotype was associated with reduced pain at 1 month at rest (GA vs AA: OR = 4.329, 95%CI = 1.523-12.310, P = .006), 6 months at rest and in movement (GA vs AA at rest: OR = 4.642, 95%CI = 1.535-14.040, P = .007; GA vs AA in movement: OR = 3.509, 95%CI = 1.169-10.530, P = .025), and 12 months in movement (GA vs AA: OR = 5.754, 95%CI: 1.492-22.200, P = .011). In contrast, the rs2236742 AA genotype was associated with increased pain at all three time points ( P < .05). Carriers of rs2236742 AA also reported greater preoperative informational anxiety (GG vs AA: OR = 0.193, 95%CI: 0.049-0.758, P = .018). CTSG activity was lower in rs2070697 A-allele carriers ( P = .03). CTSG activity and pain showed no causal association. No significant relationships were found for rs45567233. CONCLUSIONS: Variants appear to modulate susceptibility to prolonged post-sternotomy pain. These findings warrant validation in larger multi-ethnic cohorts to clarify mechanisms and potential implications for personalized perioperative pain management.