Additional evidence supports association of common genetic variants in MMP3 and TIMP2 with increased risk of chronic Achilles tendinopathy susceptibility



      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.


      Case-control genetic association study.


      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.


      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).


      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.


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        • Cook J.L.
        • Khan K.M.
        • Purdam C.
        Achilles tendinopathy.
        Man Ther. 2002; 7: 121-130
        • Kujala U.M.
        • Sarna S.
        • Kaprio J.
        Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes.
        Clin J Sport Med. 2005; 15: 133-135
        • Pufe T.
        • Petersen W.J.
        • Mentlein R.
        • Tillmann B.N.
        The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease.
        Scand J Med Sci Sports. 2005; 15: 211-222
        • Magnan B.
        • Bondi M.
        • Pierantoni S.
        • Samaila E.
        The pathogenesis of Achilles tendinopathy: a systematic review.
        Foot Ankle Surg. 2014; 20: 154-159
        • Vaughn N.H.
        • Stepanyan H.
        • Gallo R.A.
        • Dhawan A.
        Genetic factors in tendon injury: a systematic review of the literature.
        Orthop J Sports Med. 2017; 5 (2325967117724416)
        • Nell E.M.
        • van der Merwe L.
        • Cook J.
        • Handley C.J.
        • Collins M.
        • September A.V.
        The apoptosis pathway and the genetic predisposition to Achilles tendinopathy.
        J Orthop Res. 2012; 30: 1719-1724
        • September A.V.
        • Cook J.
        • Handley C.J.
        • van der Merwe L.
        • Schwellnus M.P.
        • Collins M.
        Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations.
        Br J Sports Med. 2009; 43: 357-365
        • Saunders C.J.
        • van der Merwe Lize
        • Posthumus M.
        • et al.
        Investigation of variants within the COL27A1 and TNC genes and Achilles tendinopathy in two populations.
        J Orthop Res. 2013; 31: 632-637
        • Guan F.L.
        • Zhang B.
        • Yan T.L.
        • et al.
        MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese.
        Schizophr Res. 2014; 152: 97-104
        • Liu X.S.
        • Hou Y.
        • Yan T.L.
        • et al.
        Dopamine D3 receptor-regulated NR2B subunits of N-Methyl-d-Aspartate receptors in the nucleus accumbens involves in morphine-induced locomotor activity.
        CNS Neurosci Ther. 2014; 20: 823-829
        • Zhang T.X.
        • Liu P.
        • Zhang Y.
        • et al.
        Combining information from multiple bone turnover markers as diagnostic indices for osteoporosis using support vector machines.
        Biomarkers. 2018; : 1-7
        • Saunders C.J.
        • Lize V.D.M.
        • Jill C.
        • Handley C.J.
        • Malcolm C.
        • September A.V.
        Extracellular matrix proteins interact with cell-signaling pathways in modifying risk of achilles tendinopathy.
        J Orthop Res. 2015; 33: 898-903
        • Thore Z.
        • Gilbert T.W.
        • Yoder M.C.
        • Badylak S.F.
        Extracellular matrix scaffolds are repopulated by bone marrow-derived cells in a mouse model of achilles tendon reconstruction.
        J Orthop Res. 2010; 24: 1299-1309
        • Hideaki N.
        • Robert V.
        • Gillian M.
        Structure and function of matrix metalloproteinases and TIMPs.
        Cardiovasc Res. 2006; 69: 562-573
        • Ireland D.
        • Harrall R.
        • Curry V.
        • et al.
        Multiple changes in gene expression in chronic human Achilles tendinopathy.
        Matrix Biol. 2001; 20: 159-169
        • Alfredson H.
        • Lorentzon M.S.
        • Backman A.
        • Lerner U.H.
        cDNA-arrays and real-time quantitative PCR techniques in the investigation of chronic achilles tendinosis.
        J Orthop Res. 2010; 21: 970-975
        • Fassina G.
        • Ferrari N.
        • Brigati C.
        • et al.
        Tissue inhibitors of metalloproteases: Regulation and biological activities.
        Clin Exp Metastas. 2000; 18: 111-120
        • Toth M.
        • Chvyrkova I.
        • Bernardo M.M.
        • Hernandez-Barrantes S.
        • Fridman R.
        Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes.
        Biochem Biophys Res Commun. 2003; 308: 386-395
        • Karousou E.
        • Ronga M.
        • Vigetti D.
        • Passi A.
        • Maffulli N.
        Collagens, proteoglycans, MMP-2, MMP-9 and TIMPs in human Achilles tendon rupture.
        Clin Orthop Relat Res. 2008; 466: 1577-1582
        • Raleigh S.M.
        • van der Merwe L.
        • Ribbans W.J.
        • et al.
        Variants within the MMP3 gene are associated with Achilles tendinopathy: possible interaction with the COL5A1 gene.
        Br J Sports Med. 2009; 43: 514-520
        • Khoury L.E.
        • Ribbans W.J.
        • Raleigh S.M.
        MMP3 and TIMP2 gene variants as predisposing factors for Achilles tendon pathologies: attempted replication study in a British case–control cohort.
        Meta Gene. 2016; 9: 52-55
        • Khoury L.E.
        • Posthumus M.
        • Collins M.
        • Handley C.J.
        • Cook J.
        • Raleigh S.M.
        Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study.
        J Sci Med Sport. 2013; 16: 493-498
        • Purcell S.
        • Neale B.
        • Toddbrown K.
        • et al.
        PLINK: a tool set for whole-genome association and population-based linkage analyses.
        Am J Hum Genet. 2007; 81: 559-575
        • Gabriel S.B.
        • Schaffner S.F.
        • Nguyen H.
        • et al.
        The structure of haplotype blocks in the human genome.
        Science. 2002; 296: 2225-2229
        • Dan X.
        • Alan P.B.
        • Linfeng W.
        • Jie Z.
        • Trupti K.
        • Michael S.
        Dynamic trans-acting factor colocalization in human cells.
        Cell. 2013; 155: 713-724
        • Sim N.L.
        • Kumar P.
        • Hu J.
        • Henikoff S.
        • Schneider G.
        • Ng P.C.
        SIFT web server: predicting effects of amino acid substitutions on proteins.
        Nucleic Acids Res. 2012; 40 (Web Server issue):W452-457
        • Consortium G.T.
        The Genotype-Tissue Expression (GTEx) project.
        Nat Genet. 2013; 45: 580-585
        • Han W.
        • Zhang T.X.
        • Ni T.
        • et al.
        Relationship of common variants in CHRNA5 with early-onset schizophrenia and executive function.
        Schizophr Res. 2018; S0920-9964: 30613-306133
        • Jia X.D.
        • Zhang T.X.
        • Li L.
        • et al.
        Two-stage additional evidence support association of common variants in the HDAC3 with the increasing risk of schizophrenia susceptibility.
        Am J Med Genet B Neuropsychiatr Genet. 2016; 171: 1105-1111
        • Zhang T.X.
        • Zhu L.
        • Ni T.
        • et al.
        Voltage-gated calcium channel activity and complex related genes and schizophrenia: a systematic investigation based on Han Chinese population.
        J Psychiatr Res. 2018; 106: 99-105
        • Kim S.K.
        • Roos T.R.
        • Roos A.K.
        • et al.
        Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy.
        Plos One. 2017; 12e0170422
        • Daum S.
        • Bauer U.
        • Foss H.D.
        • et al.
        Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease.
        Gut. 1999; 44: 17-25