title: Genetic Variants and Anterior Cruciate Ligament Rupture: A Systematic Review.
abstract: BACKGROUND
  Studies have shown a familial predisposition for anterior cruciate ligament (ACL) rupture and have been followed by genetic-association studies on polymorphisms in candidate genes in recent years. To date, no systematic review with a best-evidence synthesis has evaluated the influence of genetics on this devastating knee injury.
  
  
  OBJECTIVE
  Our objective was to evaluate the association between genetic variants and ACL rupture.
  
  
  METHODS
  We performed an extensive search in Embase, MEDLINE, Web of Science, Scopus, PubMed Publisher, Cochrane Register of Clinical Trials, and Google scholar up to 24 August 2015. Studies were eligible if they met the following inclusion criteria: (1) design was a case-control study, retrospective or prospective follow-up study, or a randomized controlled trial (RCT); (2) the study examined the association between a genetic variant and ACL rupture in both an ACL and a control group. We determined the risk of bias for all included studies.
  
  
  RESULTS
  We included a total of 16 studies (eight at high risk of bias and eight with an unclear risk) that examined 33 different DNA variants. Conflicting evidence was found for the COL1A1 rs1800012 and COL3A1 rs1800255 variants, whereas limited evidence was found for no association of the COL5A1 rs12722 and rs13946 and COL12A1 rs970547 variants (all encoding collagen). Evidence was insufficient to draw conclusions as to whether any other genetic variant identified in this review had any association with ACL rupture.
  
  
  CONCLUSIONS
  More research is needed to support a clear association between ACL rupture and genetic variants. Genome-wide studies are recommended for exploring more potential genetic variants. Moreover, large prospective studies are needed to draw robust conclusions.
authors.affiliation: Department of Orthopaedic Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3000 CA, Rotterdam, The Netherlands. mustafa_kaynak@live.nl.
authors.forename: Mustafa
authors.identifier: http://orcid.org/0000-0002-6840-4488
authors.initials: M
authors.lastname: Kaynak
authors.affiliation: Department of Orthopaedic Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Nijman
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: van Meurs
authors.affiliation: Department of Orthopaedic Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Reijman
authors.affiliation: Department of Orthopaedic Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Meuffels
mesh_terms: D016118:Anterior Cruciate Ligament; D059549:Anterior Cruciate Ligament Reconstruction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007718:Knee Injuries; D012421:Rupture / Q000235:genetics*