EXPRESS: CYP gene variants show preliminary evidence of association with patient-reported outcomes in active-duty service members with chronic pain

Chronic pain is highly prevalent among active-duty service members (ADSMs) and contributes to substantial physical, psychological, and social burden. Genetic factors are recognized as central to pain susceptibility and treatment response. While few studies have examined the genes involved in cortisol synthesis, changes in the coding of cytochrome P450 (CYP) enzymes responsible for cortisol production have been implicated in chronic pain. We evaluated whether exonic variants in CYP11B1 and CYP17A1 are associated with salivary cortisol and pain-related outcomes in ADSMs with chronic pain using baseline genomic, salivary cortisol, and web survey data from 118 participants in a pragmatic clinical trial. We identified 40 variants across CYP11B1 and CYP17A1 exons and examined both common and rare variant burden scores. Linear regression models estimated associations with 11 outcomes, including pain intensity, sleep-related impairment, depression, and physical and social functioning. Mediation by cortisol was also assessed. Variants in both genes showed consistent associations with pain outcomes. Rare CYP11B1 variants (minor allele frequency < 5%) demonstrated the strongest relationships with pain intensity, pain impact, depression, fatigue, and sleep-related impairment. CYP17A1 variants were strongly associated with sleep-related impairment, depression, fatigue, anxiety, and pain impact. Rare CYP11B1 variants were associated with salivary cortisol; however, mediation analyses indicated that cortisol accounted for only a modest proportion (4%-18%) of the gene-pain associations. These exploratory findings suggest that functional variation in cortisol-related CYP genes may contribute to pain-related outcomes among ADSMs with chronic pain, warranting replication in larger cohorts. The research protocol was registered in ClinicalTrials.gov (NCT03297905).