Association of estrogen receptor ß polymorphisms with posterior tibial tendon dysfunction.

Posterior tibial tendon (PTT) dysfunction is three times more common in females, and some patients may have a predisposition without a clinically evident cause, suggesting that individual characteristics play an important role in tendinopathy. The present study investigated the association of rs4986938 (+ 1730G > A; AluI RFLP) and rs1256049 (- 1082G > A; RsaI RFLP) single nucleotide polymorphisms (SNPs) of estrogen receptor-beta (ER-ß) gene with PTT dysfunction. A total of 400 participants were recruited. The PTT dysfunction group: these patients underwent surgery, with PTT tendinopathy confirmed by histopathology and magnetic resonance image (MRI). The control group was composed of participants with no clinical or MRI evidence of PTT dysfunction. Each group was composed of 100 postmenopausal women, 50 premenopausal women, and 50 men. Genomic DNA was extracted from saliva samples, and genotypes were obtained by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Concerning the ER-ß SNP rs4986938, there were significant differences in the frequencies of alleles between test and control groups of all the cases, only postmenopausal women and only men (p < 0.0001, p = 0.0016 and p = 0.0001). Considering the PTT dysfunction group and comparing postmenopausal women versus premenopausal women adding men, the analysis showed significant differences in the allelic distribution (p = 0.0450): the allele A in postmenopausal women is a risk factor. The ER-ß SNP rs1256049 did not show differences in the frequencies of alleles and genotypes between groups. The ER-ß SNP rs4986938, but not ER -ß SNPs rs1256049, may contribute to PTT insufficiency in the Brazilian population, with additional risk in postmenopausal women. Addition, in men the genetic factor could be more determinant.

Fc receptor-like 3 (-169T>C) polymorphism increases the risk of tendinopathy in volleyball athletes: a case control study.

BACKGROUND: Tendinopathy 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. METHODS: This 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. RESULTS: Tendinopathy 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. CONCLUSIONS: FCRL3 -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.

Vascular Endothelial Growth Factor Receptor-2 Polymorphisms Have Protective Effect against the Development of Tendinopathy in Volleyball Athletes.

The aim of the study was to investigate whether genetic variants in VEGF and KDR genes can be correlated with susceptibility of tendinopathy in volleyball athletes. This study was conducted at the Brazilian Volleyball Federation, and comprised 179 volleyball athletes: 88 had a confirmed diagnosis of tendinopathy (cases), whereas 91 had no evidence of the disease (controls). The VEGF (-2578C>A, -460T>C and +936C>T) and KDR (-604C>T, 1192G>A and 1719T>A) polymorphisms were determined by TaqMan real-time polymerase chain reaction. The odds ratio (OR) with their 95% confidence intervals (CI) were calculated using an unconditional logistic regression model. The evaluation of demographic and clinical characteristics revealed the athlete age (P < 0.001), years of practice in volleyball (P < 0.001) and presence of pain (P = 0.001) were risk factors for tendinopathy. KDR 1192 GA and GA + AA genotypes were associated with lower risk of tendinopathy (OR: 0.41, 95% CI: 0.19-0.88 and OR: 0.47, 95% CI: 0.23-0.98, respectively). The KDR (-604C>T, 1192G>A and 1719T>A) haplotypes CGA and CAT were associated with decreased tendinopathy risk (OR: 0.46, 95% CI: 0.21-0.99 and OR: 0.23, 95% CI: 0.07-0.76, respectively). With regards to pain, traumatic lesion and away from training due to injury, VEGF and KDR polymorphisms were not associated with clinical symptoms complaints. The present results provide evidence that the KDR polymorphisms were associated with development of tendinopathy, and can contribute to identify new therapeutic targets or personalized training programs to avoid tendinopathy development in athletes.

Posterior tibial tendinopathy associated with matrix metalloproteinase 13 promoter genotype and haplotype.

BACKGROUND: Posterior tibial tendon (PTT) is particularly vulnerable and its insufficiency is recognized as the main cause of adult acquired flat foot. Some patients have a predisposition without a clinically recognized cause, suggesting that individual characteristics play an important role in tendinopathy. The present study investigated whether genetic variants in matrix metalloproteinases (MMPs) are associated with PTT dysfunction. METHODS: One hundred women who presented PTT dysfunction, with histopathological examination of the tendon and magnetic resonance imaging (MRI) confirming tendinopathy, as well as 100 asymptomatic women who presented intact PPT as assessed by MRI and constituting the control group, were evaluated for MMP-13 g.-77 A > G (rs2252070) polymorphism, individually and in haplotypes, as well as in combination with MMP-1 g.-519 A > G (rs1144393), MMP-1 g.-1607 G > GG (rs1799750) and MMP-8 g.-799 C > T (rs11225395) polymorphisms with PTT dysfunction. Genomic DNA was extracted from the saliva and genotypes were obtained by polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the results included a Mann-Whitney U-test, Fisher's exact test, multiple logistic regression, chi-squared and SNPstats software (http://bioinfo. iconcologia.net/snpstats/start.htm). p < 0.05 was considered statistically significant. RESULTS: The A allele frequency (MMP-13 g.-77 A > G (rs2252070) polymorphism) was significantly higher in the case group (76% and 61%, respectively; p = 0.010, odds ratio = 2.02; 95% confidence interval = 1.32-3.12). The genotype distribution was also significantly different between groups (p = 0.001, odds ratio = 2.82; 95% confidence interval = 1.58-5.02). Global haplotype analysis indicated a significant difference between both groups. CONCLUSIONS: In conclusion, these findings indicate that MMP-13 g.-77 A > G (rs2252070) polymorphism individually, as well as its haplotypes MMP-1 g.-519 A > G (rs1144393), MMP-1 g.-1607 G > GG (rs1799750) and MMP-8 g.-799 C > T (rs11225395), may contribute to PTT dysfunction.

BMP4 and FGF3 haplotypes increase the risk of tendinopathy in volleyball athletes.

OBJECTIVES: To investigate whether genetic variants can be correlated with tendinopathy in elite male volleyball athletes. DESIGN: Case-control study. METHODS: Fifteen single nucleotide polymorphisms within BMP4, FGF3, FGF10, FGFR1 genes were investigated in 138 elite volleyball athletes, aged between 18 and 35 years, who undergo 4-5h of training per day: 52 with tendinopathy and 86 with no history of pain suggestive of tendinopathy in patellar, Achilles, shoulder, and hip abductors tendons. The clinical diagnostic criterion was progressive pain during training, confirmed by magnetic resonance image. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped using TaqMan real-time PCR. Chi-square test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of covariates and incidence of tendinopathy. RESULTS: Statistical analysis revealed participant age (p=0.005) and years of practice (p=0.004) were risk factors for tendinopathy. A significant association between BMP4 rs2761884 (p=0.03) and tendinopathy was observed. Athletes with a polymorphic genotype have 2.4 times more susceptibility to tendinopathy (OR=2.39; 95%CI=1.10-5.19). Also, association between disease and haplotype TTGGA in BMP4 (p=0.01) was observed. The FGF3 TGGTA haplotype showed a tendency of association with tendinopathy (p=0.05), and so did FGF10 rs900379. FGFR1 showed no association with disease. CONCLUSIONS: These findings indicate that haplotypes in BMP4 and FGF3 genes may contribute to the tendon disease process in elite volleyball athletes.

MMP-8 polymorphism is genetic marker to tendinopathy primary posterior tibial tendon.

Posterior tibial tendon is particularly vulnerable and is responsible for much morbidity in sportspersons. Some patients have a predisposition without a clinically recognized cause, suggesting that individual characteristics, inclusive genetic inheritance, play an important role in tendinopathy. Matrix metalloproteinase (MMP)-8 is a proteinase capable of degrading a large amount of extracellular proteins, and influence degradation and remodeling of collagen. To determine whether the -799 polymorphism in the promoter of MMP-8 gene is associated with tendinopathy in posterior tibial tendon, 50 patients undergoing surgical procedures and anatomopathological diagnosis of degenerative lesions of the posterior tibial tendon and 100 control patients with posterior tibial tendon integrity and without signs of degeneration in magnetic resonance imaging were evaluated for the -799 MMP-8 polymorphism. There was a significant difference in the presence of the different alleles (P = 0.001) and genotype (P = 0.003) between the control group and the test group for the MMP-8 gene. The polymorphism at position -799 of the gene for MMP-8 is associated with tendinopathy primary posterior tibial tendon in the population studied. The results suggest that individuals with the T allele are at greater risk of developing tendinopathy.

Evidence of genetic variations associated with rotator cuff disease.

BACKGROUND: Rotator cuff disease (RCD) is a complex process influenced by a multitude of factors, and a number of gene pathways are altered in rotator cuff tears. Polymorphisms in these genes can lead to an extended tendon degeneration process, which explains why subsets of patients are more susceptible to RCD. MATERIALS AND METHODS: Twenty-three single-nucleotide polymorphisms within 6 genes involved in repair and degenerative processes (DEFB1, DENND2C, ESRRB, FGF3, FGF10, and FGFR1) were investigated in 410 patients, 203 with a diagnosis of RCD and 207 presenting with absence of RCD. Exclusion criteria were patients older than 60 years and younger than 45 years with a history of trauma, rheumatoid arthritis, autoimmune syndrome, pregnancy, and use of corticosteroids. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped with TaqMan real-time polymerase chain reaction. The χ(2) test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of many covariates and the incidence of RCD. RESULTS: Statistical analysis revealed female sex (P = .001; odds ratio, 2.07 [1.30-3.30]) and being white (P = .002; odds ratio, 1.88 [1.21-2.90]) to be risk factors for RCD development. A significant association of haplotypes CCTTCCAG in ESRRB (P = .05), CGACG in FGF3 (P = .01), CC in DEFB1 (P = .03), and FGFR1 rs13317 (P = .02) with RCD could be observed. Also, association between FGF10 rs11750845 (P = .03) and rs1011814 (P = .01) was observed after adjustment by ethnic group and sex. CONCLUSIONS: Our work clearly supports the role of DEFB1, ESRRB, FGF3, FGF10, and FGFR1 genes in RCD. Identification of these variants can clarify causal pathways and provide a clue for therapeutic targets.

MMP-1 promoter polymorphism is associated with primary tendinopathy of the posterior tibial tendon.

Posterior tibial tendon (PTT) dysfunction is recognized as an etiology leading to acquired flatfoot in adults, causing significant functional loss. Many risk factors and systemic conditions have been proposed in literature. However, many patients present PTT dysfunction without any of these characteristics. This suggests that there could be a genetic influence associated with posterior tibial tendinopathy. The purpose of the present study is to investigate the association of the -1607 polymorphism in the promoter gene of MMP-1 and posterior tibial tendinopathy. The test group included 50 women, who presented PTT dysfunction grade 2 or 3, and who were submitted to surgical treatment, with histopathological examination of the tendon and magnetic resonance image (MRI) confirming tendinopathy, while the control group was 100 asymptomatic women who presented intact PTT at MRI. The results were analyzed using the chi-square test. The data showed a 75% incidence of the allele 1G and 62% of the genotype 1G/1G at the control group while, at the test group, they showed a 78% incidence of the allele 2G and 72% of the genotype 2G/2G (p < 0.001). The -1607 polymorphism of promoter gene of MMP-1 is associated with the posterior tibial tendinopathy in the studied population.

Low-level laser therapy in experimental model of collagenase-induced tendinitis in rats: effects in acute and chronic inflammatory phases.

A variety of treatments for tendinopathies is currently used or has been trialed. However, in fact, there is a remarkably little evidence that any conventional therapies are effective. In the last years, low-level laser therapy (LLLT) has been showing interesting results in inflammatory modulation in different musculoskeletal disorders, but the optimal parameters and mechanisms behind these effects are not fully understood. The aim of this study is to investigate if the LLLT modulates the acute and chronic phase of collagenase-induced tendinitis in rat by interfering in mRNA expression for matrix metalloproteinases (MMP13 and MMP1), vascular endothelial growth factor (VEGF), and anti-inflammatory mediator (interleukin (IL)-10). For such, tendinitis was induced by collagenase injection in male Wistar rats. Animals were treated with LLLT (780 nm, potency of 22 mW, 107 mW/cm(2), energy density of 7.5 J/cm(2), and energy delivered of 1.54 J) with different number of treatments in accordance with the inflammatory phase analyzed. LLLT was able to modulate mRNA gene expression of IL-10, VGEF, MMP1, and MMP13 both in acute than in chronic inflammatory phase (p<0.05). Our results suggest that LLLT with parameters employed in the present study was able to modulate IL-10, VEGF, MMP1, and MMP13 mRNA gene expression both in acute than in chronic tendon inflammation. However, further studies are needed to establish optimal parameters for LLLT.

Low-level laser therapy (LLLT; 780 nm) acts differently on mRNA expression of anti- and pro-inflammatory mediators in an experimental model of collagenase-induced tendinitis in rat.

Low-level laser therapy (LLLT) has been found to produce anti-inflammatory effects in a variety of disorders. Tendinopathies are directly related to unbalance in expression of pro- and anti-inflammatory cytokines which are responsible by degeneration process of tendinocytes. In the current study, we decided to investigate if LLLT could reduce mRNA expression for TNF-α, IL-1ß, IL-6, TGF-ß cytokines, and COX-2 enzyme. Forty-two male Wistar rats were divided randomly in seven groups, and tendinitis was induced with a collagenase intratendinea injection. The mRNA expression was evaluated by real-time PCR in 7th and 14th days after tendinitis. LLLT irradiation with wavelength of 780 nm required for 75 s with a dose of 7.7 J/cm(2) was administered in distinct moments: 12 h and 7 days post tendinitis. At the 12 h after tendinitis, the animals were irradiated once in intercalate days until the 7th or 14th day in and them the animals were killed, respectively. In other series, 7 days after tendinitis, the animals were irradiated once in intercalated days until the 14th day and then the animals were killed. LLLT in both acute and chronic phases decreased IL-6, COX-2, and TGF-ß expression after tendinitis, respectively, when compared to tendinitis groups: IL-6, COX-2, and TGF-ß. The LLLT not altered IL-1ß expression in any time, but reduced the TNF-α expression; however, only at chronic phase. We conclude that LLLT administered with this protocol reduces one of features of tendinopathies that is mRNA expression for pro-inflammatory mediators.