Cytokine Gene Variants Are Associated With Aerobic Fitness-Related, Hematological, and Metabolic Traits in Healthy Adults

Genetic variation in cytokine genes may influence cytokine-related signaling, metabolism, and exercise-related phenotypes, 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 tumor necrosis factor-alpha (TNF-α; rs1800629) associate with physiological, biochemical, and performance-related traits in healthy adults. For VO2max-stratified analyses, 501 healthy Polish adults underwent physiological, biochemical, and genomic assessments, classified by maximal oxygen uptake using sex-and age-adjusted reference categories. Whole-cohort analyses were performed for biochemical and hematological traits in up to 962 participants. IL6 rs1800795 CC genotype showed an exploratory higher serum-iron (p = 0.004) and hematocrit (p = 0.033). The IL6 C-G-G haplotype (rs1800795-rs1800796-rs1800797) was associated with higher serum-iron (p = 0.0012, within-phenotype FDR-adjusted p = 0.002). TNF-α rs1800629, showed a model-dependent association with lower aerobic fitness classification in grouped analyses (p = 0.006). A-allele carriers had lower odds of higher-fitness classification under the dominant model and AG heterozygotes showed the strongest association under overdominant model. Grouped analyses; AG heterozygotes (p = 0.037) had higher LDL cholesterol, was not retained in whole-cohort adjusted-analyses. IL15 showed no single-locus effects but an exploratory multi-locus genotype combination, IL15 CC/CT × TNF-α GG, associated with higher odds of aerobic fitness classification (p = 0.004). Whole-cohort analyses: IL6 rs1800795 was associated with serum-iron, hematocrit, hemoglobin, and RBC after adjustments. Findings provide preliminary evidence of modest, trait-specific associations between cytokine-related genetic variation and hematological, metabolic, and aerobic fitness-related phenotypes. IL6 rs1800795 mainly associated with iron-related and hematological traits; TNF-α rs1800629 findings were model-dependent and inconsistent. IL15 CC/CT × TNF-α GG combination is exploratory, requiring independent replication.