Journal of Science and Medicine in Sport 16 (2013) 493–498 Contents lists available at ScienceDirect Journal of Science and Medicine in Sport journal homepage: www.elsevier.com/locate/jsams Original research Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: A genetic association study Louis El Khoury a , Michael Posthumus b , Malcolm Collins b,c , Christopher J. Handley d , Jill Cook e , Stuart M. Raleigh a,∗ a The Division of Health and Life Sciences, University of Northampton, Northampton, UK b Department of Human Biology, UCT/MRC Research Unit for Exercise Science and Sports Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa c South African Medical Research Council, Cape Town, South Africa d School of Human Biosciences and the Musculoskeletal Research Centre, La Trobe University, Melbourne, Victoria, Australia e Department of physiotherapy, School of Primary Health Care, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia article info Article history: Received 5 December 2012 Received in revised form 4 February 2013 Accepted 10 February 2013 Keywords: A disintegrin and metalloproteinase A disintegrin and metalloproteinase with thrombospondin motifs Tissue inhibitor metalloproteinase Gene Tendinopathy abstract Objectives: Achilles tendon pathology (ATP) is a multifactorial condition for which genetic risk factors have been identified. The ADAMTS, ADAM12 and TIMP2 genes encode enzymes that are important regulators of tendon homeostasis. ADAMTS2 and ADAMTS14 proteins are procollagen N-propeptidases for pro- collagen type I, type II, and type III. ADAMTS2, like COL5A1, has been linked to Ehlers–Danlos syndrome. Variants within ADAMTS5 and ADAM12 have been associated with osteoarthritis. TIMP2, a metallopro- tease inhibitor, maintains homeostasis in the ECM by inhibiting ADAM, ADAMTS and MMP functions. We sought to determine whether single nucleotide polymorphisms (SNPs) within the ADAMTS2, ADAMTS5, ADAMTS14, ADAM12 and TIMP2 genes were associated with the risk of ATP in two independent popula- tions. Design: 213 (115 ATP cases and 98 asymptomatic controls) South African Caucasian participants and 209 (60 ATP cases and 149 asymptomatic controls) Australian Caucasian participants were recruited for this case–control genetic association study. Methods: All participants were genotyped using TaqMan technology for the ADAMTS2 rs1054480, ADAMTS5 rs226794, ADAMTS14 rs4747096, ADAM12 rs3740199, and TIMP2 rs4789932 SNPs. Results: We report for the first time a significant (p = 0.016) genotypic association between the TIMP2 rs4789932 variant and ATP in a combined Caucasian cohort. We also identify an interaction between the ADAMTS14 rs4747096 variant and age of onset of ATP (p = 0.024). Conclusions: Our data show that DNA sequence variation within the TIMP2 gene is a risk factor for ATP in Caucasians. Furthermore, carriage of the ADAMTS14 rs4747096 GG variant appears to delay onset of the injury in the ATP group. © 2013 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved. 1. Introduction Achilles tendon pathology (ATP), consisting of chronic Achilles tendinopathy and acute Achilles tendon ruptures, typically occurs as a result of acute or repetitive mechanical loading during occu- pational and sporting activities. 1 Although the exact underlying aetiology of ATP remains to be defined, a number of intrinsic (including genetic) and extrinsic risk factors have been identified. 2 ∗ Corresponding author at: Division of Health and Life Sciences, University of Northampton, Park Campus, Northampton NN2 7AL, UK. E-mail address: stuart.raleigh@northampton.ac.uk (S.M. Raleigh). Previous studies have shown that variants within the TNC, 3 COL5A1, 4,5 MMP3, 6 GDF5, 7 and CASP8 genes 8 independently asso- ciate with the risk of ATP. Since ATP is a multifactorial condition, its development is likely to have a complex genetic component and additional candidate genes should be investigated. 1 All genes which have been shown to associate with Achilles tendinopathy to date encode for proteins that are either structural and/or regulatory in function. 1 Additional genes encoding for extracellular matrix (ECM) specific proteinases and their inhibitors are therefore good candidates for further investigation. In addition to the MMP family of proteins, the ADAM (a disintegrin and metalloproteinase), ADAMTS (a disintegrin and metalloproteinase 1440-2440/$ – see front matter © 2013 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsams.2013.02.006