Gene Polymorphism Of IL-6 And MMP-3 Decreases The ROM After Rotator Cuff Repair

BackgroundRotator cuff (RC) injuries in the shoulder account for overuse injuries in sports as well as in jobs that require repetitive activity, which accounts for more than 4.5 millions physician visits per yea. Excessive mechanical loading is considered the major causation factor. When RC tears are symptomatic and non-operative management fails, they are typically repaired surgically.Post-operative stiffness, also known as adhesive capsulitis (AC), is affected by many factors including patient comorbidities such as diabetes mellitus, proneness to scar formation, preoperative shoulder stiffness, surgical technique, and postoperative rehabilitation. Importantly, the fact is not all patients face the problem of post-operative stiffness and not all patients face the same severity. It seems the genetic factors may play an important role in it, among which, the single nuclear polymorphism (SNP) may be involved. Previous results demonstrate that levels of inflammatory (interleukin 6, IL-6) and fibrogenic cytokines (Matrix metalloproteinases 3, MMP-3) are elevated in the synovium of patients with AC compared with controls. Given the genetic factors like SNP may be involved in the pathologies of post-operative stiffness, the gene polymorphism of IL-6 and MMP-3, which are elevated in AC, may associated with the risk of post-operative stiffness. The present study aims to investigate whether variants within the IL-6 and MMP-3 gene contributed to post-operative stiffness in a Chinese Han population.ObjectivePost-operative stiffness is common after rotator cuff repair, given the difference in susceptibility and severity, the genetic factors may be involved. Interleukin 6 (IL-6) and Matrix metalloproteinases 3 (MMP-3) were previous found as key cytokines in the pathologies of adhesive capsulitis. Accordingly, this study aims to determine whether the IL-6 SNPs(rs10499563, rs180-0796) and MMP-3 SNPs (rs679620, rs591058 and rs650108) were associated with post-operative stiffness in Chinese Han Populations.MethodsA total of 188 patients diagnosed with rotator cuff tears treated with mini-open surgery were enrolled in this study, among which 87 patients were diagnosed as post-operative stiffness and the remaining 101 patients as controls. All subjects included in this study were Chinese Han Population. Each patient was treated with mini-open repair technique by the same operator. All patients undergo the same postoperative rehabilitation protocols. All subjects were genotyped for IL-6 and MMP-3 SNPs.Results1、The patients were grouped according to the ROM evaluation at 3 months post-operative. The definition of the post-operative stiffness was the limitation of passive motion in at least 2 directions (abduction and forward flexion<100°, external rotation<20°, or internal rotation<L3) in this study. As a result, among the 188 patients,87 patients was diagnosed as post-operative stiffness and the remaining 101 patients defined as controls. There were no significant differences between groups in terms of age, gender, dominant arm, diabetes/hypertension/thyroid dis-ease status, smoking, and pre-operation stiffness status. However, the patients with post-operative stiffness appeared to suffer from larger cuff tear than the patients with no post-operative stiffness (P=0.043).2、Association of IL-6 and MMP-3 polymorphisms with post-operative stiffness susceptibilityAs expected, the distribution of the genotypes of SNPs of IL-6 and MMP-3 gene conformed to the Hardy-Wei nberg equilibrium and the genotyping success rate was 100%.For the analysis of the IL-6 SNPs, no statistical association was found for the rs10499563 SNP no matter which genetic model was used. For the rs1800796 SNP, the increased G allele was found significantly associated with increased susceptibility of post-operative stiffness with the allele level comparison (P<0.0001), with dominant model comparison (P=0.028), and with the extreme genotype comparison (P=0.030). But no statistical difference was found with the recessive model comparison (P=0.070), which may be a result of the relatively small population.For the analysis of the MMP-3 SNPs, the increased A allele in rs679620 SNP was found significantly associated with increased incidence rate of post-operative stiffness, no matter with the allele level comparison (P<0.0001), with dominant model comparison (P=0.038), with recessive model comparison (P=0.010), or with the extreme genotype comparison (P=0.005). For the rs650108 SNP of MMP-3, the significant association was only found with the extreme genotype comparison (OR=2.551,95% CI 1.109-5.868, P=0.037) and the allele level comparison (OR=1.62,95% CI 1.356-1.936, P<0.0001). And no statistical association was found for the rs591058 SNP no matter which genetic model was used.3、Association of IL-6 and MMP-3 Polymorphisms with post-operative stiffness severityAs only the rs1800796 SNP of IL-6 and rs679620 SNP of MMP-3 were found to be associated with the risk of post-operative stiffness, these two SNPs were chose to be analyzed in association with post-operative stiffness severity. And the forward flexion was selected as the definition of the severity of stiffness. One way ANOVA analysis found that there was a significant decreased forward flexion degree in correction with the minor allele of the SNP rs1800796 (P<0.0001) and SNP rs679620 (P<0.0001).ConclusionThe rs1800796 SNP of IL-6 and rs650108 SNP of MMP-3 were associated with increased risk of post-operative stiffness susceptibility and severity. This finding can be used in guiding the rehabilitation procedure after rotator cuff surgery, in another word, those with the genetic susceptibility factors should receive a more radical rehabilitation procedure and those without the susceptibility factors can be more conservative.