Abstract
BackgroundTendinopathy pathogenesis is associated with inflammation. Regulatory T (Treg) cells contribute to early tissue repair through an anti-inflammatory action, with the forkhead box P3 (FOXP3) transcription factor being essential for Treg function, and the FC-receptor-like 3 (FCRL3) possibly negatively regulating Treg function. FCRL3 –169T>C and FOXP3 –2383C>T polymorphisms are located near elements that regulate respective genes expression, thus it was deemed relevant to evaluate these polymorphisms as risk factors for tendinopathy development in athletes.MethodsThis case-control study included 271 volleyball athletes (146 tendinopathy cases and 125 controls) recruited from the Brazilian Volleyball Federation. Genotyping analyses were performed using TaqMan assays, and the association of the polymorphisms with tendinopathy evaluated by multivariate logistic regression.ResultsTendinopathy frequency was 63% patellar, 22% rotator cuff and 15% Achilles tendons respectively. Tendinopathy was more common in men (OR = 2.87; 95% CI = 1.67–4.93). Higher age (OR = 8.75; 95% CI = 4.33–17.69) and more years of volleyball practice (OR = 8.38; 95% CI = 3.56–19.73) were risk factors for tendinopathy. The FCRL3 –169T>C frequency was significantly different between cases and controls. After adjustment for potential confounding factors, the FCRL3 –169C polymorphism was associated with increased tendinopathy risk (OR = 1.44; 95% CI = 1.02–2.04), either considering athletes playing with tendon pain (OR = 1.98; 95% CI = 1.30–3.01) or unable to train due to pain (OR = 1.89; 95% CI = 1.01–3.53). The combined variant genotypes, FCRL3 –169TC or –169CC and FOXP3 –2383CT or –2383TT, were associated with an increased risk of tendinopathy among athletes with tendon pain (OR = 2.24; 95% CI: 1.14–4.40 and OR = 2.60; 95% CI: 1.11–6.10). The combined analysis of FCRL3 –169T>C and FOXP3 –2383C>T suggests a gene-gene interaction in the susceptibility to tendinopathy.ConclusionsFCRL3 –169C allele may increase the risk of developing tendinopathy, and together with knowledge of potential risk factors (age, gender and years playing) could be used to personalize elite athletes’ training or treatment in combination with other approaches, with the aim of minimizing pathology development risk.
Highlights
The main aim of this study was to investigate the contribution of FC-receptor-like 3 (FCRL3) –169T>C and forkhead box P3 (FOXP3) –2383C>T polymorphisms as risk factors for tendinopathy development in volleyball athletes, as well as their association with tendinopathy symptoms and sports activities
The questionnaires included questions about ethnicity, self-identified according to the classification scheme adopted by the Brazilian Census, which relies on self-perception of skin color
Based on the results of this study and the previous ones, we propose a hypothesis for the role of FCRL3 –169T>C polymorphism in the tendinopathy development (Fig. 4)
Summary
Regulatory T (Treg) cells contribute to early tissue repair through an anti-inflammatory action, with the forkhead box P3 (FOXP3) transcription factor being essential for Treg function, and the FC-receptor-like 3 (FCRL3) possibly negatively regulating Treg function. Further evidence has suggested that tendons submitted to repetitive mechanical stress and its damage to stromal tissues plays a critical role in the immune system response to regeneration [8]. The influx of immune cells and their subsequent cytokine production and the critical interactions with resident tenocytes were determinants of the inflammatory effect on the tendon repair or degeneration [9]. Several studies with animal models and tissue samples of tendinopathy patients have reinforce that the immune cells play a key role in the pathophysiology of this disease. Other studies have exposed the presence of T lymphocytes in tendinopathic tissue samples and indicated that this cell population may be more immunologically active than was previously thought [11,12,13]
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