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

Abstract

Exertional rhabdomyolysis is a complex and poorly understood entity. The inflammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker representing muscle damage. Considerable variation exists in CK response between different subjects. Genetic elements may act as predisposition factors for exertional rhabdomyolysis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A promoter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow flexor 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% confidence 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 inflammatory process of muscle damage and repair.

Practical uses of genetic profile assessment in athletic training – an illustrative case study

“…Recently, it was reported that the IL-6 G-174 C genotype is associated with CPK activity in a dose-dependent fashion [40]. Individuals with one or more of the C allele had reduced exercise-associated IL-6 production, reduced post-exercise anti-inflammatory response, and as a result, higher post-exercise CPK peak, compared with individuals homozygous for the G allele.…”

“…The IL6-174 G/C polymorphism is associated with power sports performance, with the G allele exerting a favorable effect without an effect on endurance performance [33]. This could be due to the G allele-associated improved muscle repair response after eccentric damage [40]. The NOS3 gene encodes NO synthase.…”

IL6 genotype and creatine kinase response to exercise

“…Dear Editor, Yamin and colleagues recently reported an association of a common single nucleotide polymorphisms (SNP) in the promoter region of interleukin-6 (IL6) gene creating a change from a G to C at position -174, and that of tumor necrosis alpha (TNF) gene creating a change from a G to A at position -308 with systemic creatine kinase response to eccentric exercise (Yamin et al 2008).…”

“…However, in the paper Yamin et al (2008) erroneously refer to this polymorphism with a NCBI reference SNP ID rs13447445, which is in fact located at position -61 of the IL6 gene, and not at position -174 with an ID rs1800795. Similarly, the TNF SNP -308 investigated by the authors should be referred with rs1800629, and not with rs361525 which is located at position -238.…”

“…Hence this raises a concern and argues whether the relatively low frequency for genotype CC reported (0.03) (Yamin et al 2008) can rather be explained by technical limitations of the assay or data interpretation than true characteristics of the population investigated. Fortunately, genotyping assays are available that can better overcome such potential pitfalls (Marras et al 1999;Sylvain et al 2004).…”