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

Objectives

Genetic 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-α ; rs1800629) are associated with physiological, biochemical, and performance-related traits in healthy adults.

Methods

A 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.

Results

Carriers 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-α 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 × TNF-α GG combination was associated with greater odds of higher aerobic capacity (p = 0.004).

Conclusion

These findings reveal modest but consistent genetic influences on iron metabolism, lipid profile, and aerobic capacity. Variants in IL6 and TNF-α were linked to performance-relevant traits, while a multi-locus IL15 × TNF-α 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 TOPIC

• Genes that regulate inflammation, such as interleukin-6 ( IL6 ), interleukin-15 ( IL15 ) and tumour necrosis factor-alpha ( TNF-α ), may influence how people respond to exercise and recover after training.

• Prior studies were often small and compared athletes with non-athletes, rather than using an objective physiological classification like VO2max-leaving population-level links uncertain.

WHAT THIS STUDY ADDS

• In 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.

• People carrying the TNF-α A variant tended to have lower aerobic capacity, while a specific combination of IL15 and TNF-α variants was linked to better aerobic fitness (higher VO2max).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These results suggest that differences in immune-related genes partly explain why people respond differently to training.

• VO2max-based genetic profiling could support more tailored training, recovery, and prevention strategies in sport and clinical practice.