IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise

Exertional rhabdomyolysis is a complex and\ud poorly understood entity. The inflammatory system has an\ud important role in muscle injury and repair. Serum creatine\ud kinase (CK) is often used as systemic biomarker representing\ud muscle damage. Considerable variation exists in CK\ud response between different subjects. Genetic elements may\ud act as predisposition factors for exertional rhhabdomyolysis.\ud Based on their biological activity, we hypothesized that\ud in healthy subjects IL6 G-174C and TNFA G-308A promoter\ud polymorphisms would be associated with CK\ud response to exercise. We determined serum CK activity\ud pre- and post-maximal eccentric contractions of the elbow\ud flexor muscles. IL6 G-174C and TNFA G-308A genotypes\ud were analyzed for possible relationship with changes in\ud serum CK activity. IL6 G-174C genotype was associated\ud with CK activity in a dose-dependent fashion. Subjects\ud with one or more of the -174C allele had a greater increase\ud and higher peak CK values than subjects homozygous for\ud the G allele (mean +/- SE U/L: GG, 2,604 +/- 821; GC,\ud 7,592 +/- 1,111; CC, 8,403 +/- 3,849, ANOVA P = 0.0003\ud for GG + GC genotypes versus CC genotype, P = 0.0005\ud for linear trend). IL6-174CC genotype was associated with\ud a greater than threefold increased risk of massive CK\ud response (adjusted odds ratio 3.29, 95% conWdence interval\ud 1.27–7.85, P = 0.009). A milder association (P = 0.06) was\ud noted between TNFA G-308A genotype and CK activity. In\ud conclusion, we found a strong association of the IL6 G-\ud 174C genotype with systemic CK response to strenuous\ud exercise. Data suggest that homozygosity for the IL6-174C\ud allele is a clinically important risk factor for exercise-induced\ud muscle injury, further supporting the central role of\ud cytokines in the reactive inflammatory process of muscle\ud damage and repair