title: Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study.
abstract: OBJECTIVE
  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 metalloprotease 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 populations.
  
  
  METHODS
  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.
authors.affiliation: The Division of Health and Life Sciences, University of Northampton, Northampton, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: El Khoury
authors.forename: Michael
authors.initials: M
authors.lastname: Posthumus
authors.forename: Malcolm
authors.initials: M
authors.lastname: Collins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Handley
authors.forename: Jill
authors.initials: J
authors.lastname: Cook
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Raleigh
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000071096:ADAMTS Proteins; D000125:Achilles Tendon; D000328:Adult; D001315:Australia; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D052256:Tendinopathy / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D044465:White People
chemical_list: C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C447060:ADAMTS14 protein, human
keywords: A disintegrin and metalloproteinase; A disintegrin and metalloproteinase with thrombospondin motifs; Gene; Tendinopathy; Tissue inhibitor metalloproteinase