Cytokine Gene Variants Are Associated with the Inflammatory and Metabolic Profile of Human Exercise Performance

ObjectivesGenetic variation in cytokine genes may influence inflammation, metabolism, and exercise-related adaptations, yet large-scale population data remain scarce. This study examined whether five polymorphisms in interleukin-6 (IL6; rs1800795, rs1800796, rs1800797), interleukin-15 (IL15; rs1589241), and tumour necrosis factor-alpha (TNF-; rs1800629) are associated with physiological, biochemical, and performance-related traits in healthy adults. MethodsA total of 1,000 healthy adults of European ancestry underwent comprehensive physiological, biochemical, and genomic assessments. Participants were classified according to objectively measured maximal oxygen uptake (VO2max), providing a quantitative marker of aerobic capacity rather than athlete-control contrasts. ResultsCarriers of the IL6 rs1800795 CC genotype showed higher serum iron (p = 0.004) and hematocrit (p = 0.033). The IL6 C-G-G haplotype (rs1800795-rs1800796-rs1800797) was also associated with higher iron levels (p = 0.0012). For TNF- rs1800629, AG and AA genotypes were less likely to belong to the higher VO2max group (p = 0.006). AG carriers also had nominally higher LDL cholesterol (p = 0.037), while AA carriers showed a trend toward a longer time to peak power in the Wingate test (p = 0.052). No significant single-locus effects were detected for IL15, but the IL15 CC/CT x TNF- GG combination was associated with greater odds of higher aerobic capacity (p = 0.004). ConclusionThese findings reveal modest but consistent genetic influences on iron metabolism, lipid profile, and aerobic capacity. Variants in IL6 and TNF- were linked to performance-relevant traits, while a multi-locus IL15 x TNF- interaction further supports the role of cytokine-related gene networks in individual differences in aerobic fitness and recovery potential. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIGenes that regulate inflammation, such as interleukin-6 (IL6), interleukin-15 (IL15) and tumour necrosis factor-alpha (TNF-), may influence how people respond to exercise and recover after training. C_LIO_LIPrior studies were often small and compared athletes with non-athletes, rather than using an objective physiological classification like VO2max-leaving population-level links uncertain. C_LI WHAT THIS STUDY ADDSO_LIIn a study of 1,000 healthy European adults, IL6 variants were linked with higher iron and hematocrit - factors that can support oxygen transport and recovery. C_LIO_LIPeople carrying the TNF- A variant tended to have lower aerobic capacity, while a specific combination of IL15 and TNF- variants was linked to better aerobic fitness (higher VO2max). C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIThese results suggest that differences in immune-related genes partly explain why people respond differently to training. C_LIO_LIVO2max-based genetic profiling could support more tailored training, recovery, and prevention strategies in sport and clinical practice. C_LI