ACTN3 Variants Beyond Performance: Metabolic and Inflammatory Implications

Background: Athletic performance is a result of interaction between genetic and environmental factors, including training, nutrition, rest, hormonal and psychophysiological status. Numerous genes and polymorphisms can influence key physiological processes, such as muscle contractility, energy metabolism, oxidative capacity, and cardiovascular efficiency. Among these, the ACTN3 gene, and in particular the polymorphism rs1815739 (NM_001104.4:c.1729C>T; p.Arg577Ter), is well known for its association with athletic performance, but emerging evidence suggests broader effects on metabolic and inflammatory phenotypes. Methods: For this study, 109 elite athletes were enrolled and genotyped for ACTN3 c.1729C>T by Sanger sequencing. Moreover, biochemical markers, such as creatine kinase (CK), C-reactive protein (CRP), lipid profile, adiponectin, and neutrophil-to-lymphocyte ratio (NLR), were examined. Finally, to better investigate the association between genotype and athletic performance, the genotypes and the results of standardized physical tests were correlated in a small exploratory subgroup of 28 professional basketball athletes. Normality was assessed using the Shapiro-Wilk test; non-normally distributed variables were summarized as median [IQR] and analyzed with non-parametric methods. Genotype comparisons were adjusted for multiple testing using the Holm procedure, and principal biochemical models were adjusted for age, BMI, sex, and ancestry. Results: The c.1729C>T genotype distribution differed between the two ancestry groups (exact p = 0.049), and all three variants were compatible with Hardy-Weinberg equilibrium within the ancestry groups. No biochemical genotype association remained statistically significant after Holm correction. In the performance subgroup, no genotype-performance association remained significant after Holm correction. Conclusions: In this cohort, the corrected analyses did not provide robust evidence for genotype-dependent biochemical or performance effects. The results are exploratory and require replication in larger cohorts, considering ancestry and gender differences.