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

ABSTRACT

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 VO ₂ max‐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.