Eur J Appl Physiol (2008) 104:579–586 DOI 10.1007/s00421-008-0728-4 123 ORIGINAL ARTICLE IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise Chen Yamin · José Alberto Ramos Duarte · José Manuel Fernandes Oliveira · OVer Amir · Moran Sagiv · Nir Eynon · Michael Sagiv · Ruthie E. Amir Accepted: 14 March 2008 / Published online: 30 August 2008  Springer-Verlag 2008 Abstract Exertional rhabdomyolysis is a complex and poorly understood entity. The inXammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker represent- ing muscle damage. Considerable variation exists in CK response between diVerent subjects. Genetic elements may act as predisposition factors for exertional srhabdomyoly- sis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A pro- moter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow Xexor muscles. IL6 G-174C and TNFA G-308A genotypes were analyzed for possible relationship with changes in serum CK activity. IL6 G-174C genotype was associated with CK activity in a Dose-Dependent fashion. Subjects with one or more of the -174C allele had a greater increase and higher peak CK values than subjects homozygous for the G allele (mean § SE U/L: GG, 2,604 § 821; GC, 7,592 § 1,111; CC, 8,403 § 3,849, ANOVA P = 0.0003 for GG + GC genotypes versus CC genotype, P = 0.0005 for linear trend). IL6-174CC genotype was associated with a greater than threefold increased risk of massive CK response (adjusted odds ratio 3.29, 95% conWdence interval 1.27–7.85, P = 0.009). A milder association (P = 0.06) was noted between TNFA G-308A genotype and CK activity. In conclusion, we found a strong association of the IL6 G- 174C genotype with systemic CK response to strenuous exercise. Data suggest that homozygosity for the IL6-174C allele is a clinically important risk factor for exercise- induced muscle injury, further supporting the central role of cytokines in the reactive inXammatory process of muscle damage and repair. Keywords Genetics · InXammation · Polymorphisms · Cytokines · Eccentric exercise Introduction Unaccustomed exercise often causes damage in skeletal muscle that is marked by loss of muscular strength, reduced range of motion, muscle soreness and swelling, and ele- vated blood concentrations of muscle proteins [creatine kinase (CK), myoglobin] (Milne 1988; Sinert et al. 1994), a condition known as exertional rhabdomyolysis. There is an adaptation process to exercise-induced muscle injury such that less damage occurs when repeated bouts of exercise are performed by the same group of muscles within 6 months (McHugh 2003; Nosaka et al. 2001). The immune system is involved in the degeneration and regeneration process of muscle after exercise-induced mus- cle damage (MacIntyre 2001; Tidball 2005). Within the injured muscle tissue there is leukocyte inWltration and local production of the pro-inXammatory cytokines inter- leukin (IL)-1, tumor necrosis factor- (TNF-) and IL-6. IL-1 and TNF- are crucial for initiating the breakdown and the subsequent removal of damaged muscle fragments C. Yamin · M. Sagiv · N. Eynon · M. Sagiv · R. E. Amir (&) Department of Genetics and Molecular Biology, Zinman College of Physical Education and Sport Sciences at the Wingate Institute, 42902 Netanya, Israel e-mail: ruthieam@012.net.il J. A. R. Duarte · J. M. F. Oliveira CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal O. Amir Department of Cardiology, Lady Davis Carmel Medical Center, Haifa, Israel