Guanghua Nie1, Xiaodong Wen1, Xiaojun Liang1, Hongmou Zhao1, Yi Li1, Jun Lu2. 1. Department of Foot and Ankle Surgery, Honghui Hospital, Xi'an Jiaotong University, China. 2. Department of Foot and Ankle Surgery, Honghui Hospital, Xi'an Jiaotong University, China. Electronic address: junluhh@163.com.
Abstract
OBJECTIVES: To systematically evaluate the effects of matrix metalloproteinase-3 (MMP3) and tissue inhibitor of metalloproteinase-2 (TIMP2) on chronic Achilles tendinopathy (AT) susceptibility. Chronic AT is one of the most prevalent and severe injuries in athletes. Early studies suggested that tendon extracellular matrix (ECM) may be involved in the pathogenesis of chronic AT. MMP3 is an important member of the MMP family and is important to ECM integrity. In addition, tissue inhibitor of metalloproteinase-2 (TIMP2) can indirectly limit the activity of MMP3 activity. DESIGN: Case-control genetic association study. METHODS: A total of 1084 chronic AT patients and 2188 controls with Chinese Han ancestry were recruited. Twenty-one SNPs, 4 mapped to MMP3 and 17 mapped to TIMP2, were selected and genotyped. Genetic association analyses and eQTL analyses were performed. In addition, we also examined the potential effects of epistasis using a case-only study design. RESULTS: Two SNPs, rs679620 (OR=0.82, P=0.0006, MMP3) and rs4789932 (OR=1.2, P=0.0002, TIMP2) were identified to be significantly associated with chronic AT risk. No significant results were obtained from epistasis analyses. SNP rs4789932 was identified to be strongly associated with the gene expression level of TIMP2 in two types of human tissues: atrial appendage (P=0.0003) and tibial artery (P=0.0009). CONCLUSIONS: We have identified genetic polymorphisms in MMP3 and TIMP2 to be significantly associated with chronic AT risk. Further eQTL analyses indicated that SNP rs4789932 of TIMP2 was related to the gene expression levels of TIMP2. These results suggest important roles for MMP3 and TIMP2 in the pathophysiology of chronic AT.
OBJECTIVES: To systematically evaluate the effects of matrix metalloproteinase-3 (MMP3) and tissue inhibitor of metalloproteinase-2 (TIMP2) on chronic Achilles tendinopathy (AT) susceptibility. Chronic AT is one of the most prevalent and severe injuries in athletes. Early studies suggested that tendon extracellular matrix (ECM) may be involved in the pathogenesis of chronic AT. MMP3 is an important member of the MMP family and is important to ECM integrity. In addition, tissue inhibitor of metalloproteinase-2 (TIMP2) can indirectly limit the activity of MMP3 activity. DESIGN: Case-control genetic association study. METHODS: A total of 1084 chronic AT patients and 2188 controls with Chinese Han ancestry were recruited. Twenty-one SNPs, 4 mapped to MMP3 and 17 mapped to TIMP2, were selected and genotyped. Genetic association analyses and eQTL analyses were performed. In addition, we also examined the potential effects of epistasis using a case-only study design. RESULTS: Two SNPs, rs679620 (OR=0.82, P=0.0006, MMP3) and rs4789932 (OR=1.2, P=0.0002, TIMP2) were identified to be significantly associated with chronic AT risk. No significant results were obtained from epistasis analyses. SNP rs4789932 was identified to be strongly associated with the gene expression level of TIMP2 in two types of human tissues: atrial appendage (P=0.0003) and tibial artery (P=0.0009). CONCLUSIONS: We have identified genetic polymorphisms in MMP3 and TIMP2 to be significantly associated with chronic AT risk. Further eQTL analyses indicated that SNP rs4789932 of TIMP2 was related to the gene expression levels of TIMP2. These results suggest important roles for MMP3 and TIMP2 in the pathophysiology of chronic AT.
Authors: Neal L Millar; Karin G Silbernagel; Kristian Thorborg; Paul D Kirwan; Leesa M Galatz; Geoffrey D Abrams; George A C Murrell; Iain B McInnes; Scott A Rodeo Journal: Nat Rev Dis Primers Date: 2021-01-07 Impact factor: 52.329