Genetic variants involved in extracellular matrix homeostasis play a role in the susceptibility to frozen shoulder: A case‐control study

Abstract

Frozen shoulder is a condition of loss of active and passive motion as result of inflammatory contracture and fibrosis of the joint capsule. We hypothesize that genetic variants in genes involved in these processes such as genes that play a role in extracellular matrix homeostasis (collagens, glycoproteins, genes involved in TGFβ signaling, and metalloproteinases and its inhibitors) may contribute to the susceptibility to frozen shoulder. We evaluated eighteen SNPs of genes involved in extracellular matrix homeostasis in 186 cases (Nfemales = 114; Nmales = 72) of frozen shoulder and 600 age‐matched controls (Nfemales = 308; Nmales = 292). Multivariate logistic regressions were carried out with age, gender, genetic ancestry, and common comorbidities as covariates. Carriers of the C allele of MMP13 rs2252070 and G/G MMP9 (rs17576 A>G/rs17577 G>A) haplotype may have an increased risk of frozen shoulder (p = 0.002, OR = 1.64, 95%CI = 1.20–2.26, and p = 0.046, OR = 1.40, 95%CI = 1.01–1.95, respectively), especially in females (p = 0.005, OR = 1.91, 95%CI = 1.22–2.99, and p = 0.046, OR = 1.59, 95%CI = 1.01–2.51, respectively). In females, the G allele of MMP9 rs17576 tended to contribute to the susceptibility to the studied disease (p = 0.05, OR = 1.51, 95%CI = 0.97–2.33). In contrast, the presence of the C allele of TGFB1 rs1800470 seems to be associated with a reduced risk (p = 0.04, OR = 0.47, 95%CI = 0.23–0.96) while the GG‐genotype of TGFBR1 rs1590 was associated with increased risk (p = 0.027, OR = 4.11, 95%CI = 1.17–14.38) to frozen shoulder development in males. Thus, we identified genetic variants that were independent risk factors that can aid in the risk assessment of frozen shoulder reinforcing the involvement of MMP and TGFβ signaling in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis

“…The association between the SNPs and RCT risk was assessed in the following genetic models: (i) Dominant model, where the presence of the rare allele is involved in an increased or reduced risk of disease; (ii) Recessive model, where the presence of two copies of the rare allele is necessary to modify the phenotype; and (iii) Additive model, where individuals with two copies of the rare allele would be more susceptible to the disease than individuals with one copy, but individuals with one copy of the rare allele would have a greater risk of disease than individuals without the rare allele. Common homozygote genotype in the control population was defined as the reference category.…”

The puzzling pathophysiology of frozen shoulders – a scoping review

“…Besides stimulating myofibroblast differentiation, TGF-β1 also influences ECM turnover by promoting collagen synthesis. Certain genetic variants of genes for the TGF-β pathway and MMPs could be identified as risk factors for the susceptibility of FS [49]. Besides chemical stimulation by cytokines like TGF-β1, mechanical stress is also an important factor in tissue fibrosis.…”

Aspectos genéticos nas afecções do ombro

“…Only MMP13 was related to both genders. 59 MMP13, collagenase metalloproteinase, divide the main structural component of cartilage, type II collagen, thus effecting irreversible loss of Extracellular matrix (ECM) architecture and function. The expression of MMP collagenase was significantly elevated in the nodule tissue sample of patients operated for DD, where high collagen turnover occurs; however, high levels of TIMP1 blocking the action of MMP13 in the breakdown of collagen was appointed as possibly responsible for the process of contracture and fibrosis in these individuals.…”

“…Apenas a MMP13 esteve relacionada com ambos os sexos. 59 A MMP13, metaloproteinase do tipo colagenase, cliva o principal componente estrutural da cartilagem, o colágeno tipo II, efetuando, assim, a perda irreversível da arquitetura e função da Matriz extracelular (MEC). A expressão da colagenase MMP13 se mostrou significativamente elevada, na amostra de tecido de nódulos dos pacientes operados para a doença de Dupuytren, onde ocorre elevado turnover do colágeno; entretanto, elevados níveis de TIMP1 bloqueando a ação da MMP13, na quebra do colágeno, foi apontado como possível responsável pelo processo de contratura e fibrose nesses indivíduos.…”