title: Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures.
abstract: BACKGROUND
  Genetic variants within genes involved in fibrillogenesis have previously been implicated in anterior cruciate ligament (ACL) injury susceptibility. Proteoglycans also have important functions in fibrillogenesis and maintaining the structural integrity of ligaments. Genes encoding proteoglycans are plausible candidates to be investigated for associations with ACL injury susceptibility; polymorphisms within genes encoding the proteoglycans aggrecan (ACAN), biglycan (BGN), decorin (DCN), fibromodulin (FMOD) and lumican (LUM) were examined.
  
  
  METHODS
  A case-control genetic association study was conducted. 227 participants with surgically diagnosed ACL ruptures (ACL group) and 234 controls without any history of ACL injury were genotyped for 10 polymorphisms in 5 proteoglycan genes. Inferred haplotypes were constructed for specific regions.
  
  
  RESULTS
  The G allele of ACAN rs1516797 was significantly under-represented in the controls (p=0.024; OR=0.72; 95% CI 0.55 to 0.96) compared with the ACL group. For DCN rs516115, the GG genotype was significantly over-represented in female controls (p=0.015; OR=9.231; 95%CI 1.16 to 73.01) compared with the ACL group and the AA genotype was significantly under-represented in controls (p=0.013; OR=0.33; 95% CI 0.14 to 0.78) compared with the female non-contact ACL injury subgroup. Haplotype analyses implicated regions overlapping ACAN (rs2351491 C>T-rs1042631 T>C-rs1516797 T>G), BGN (rs1126499 C>T-rs1042103 G>A) and LUM-DCN (rs2268578 T>C-rs13312816 A>T-rs516115 A>G) in ACL injury susceptibility.
  
  
  CONCLUSIONS
  These independent associations and haplotype analyses suggest that regions within ACAN, BGN, DCN and a region spanning LUM-DCN are associated with ACL injury susceptibility. Taking into account the functions of these genes, it is reasonable to propose that genetic sequence variability within the genes encoding proteoglycans may potentially modulate the ligament fibril properties.
authors.affiliation: UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Division of Human Genetics, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Sasha
authors.initials: S
authors.lastname: Mannion
authors.affiliation: UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Asanda
authors.initials: A
authors.lastname: Mtintsilana
authors.affiliation: UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Sports Science Orthopaedic Clinic, Cape Town, South Africa.
authors.forename: Michael
authors.initials: M
authors.lastname: Posthumus
authors.affiliation: Sports Science Orthopaedic Clinic, Cape Town, South Africa.
authors.forename: Willem
authors.initials: W
authors.lastname: van der Merwe
authors.affiliation: Sports Science Orthopaedic Clinic, Cape Town, South Africa.
authors.forename: Hayden
authors.initials: H
authors.lastname: Hobbs
authors.affiliation: UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa The South African Medical Research Council, Cape Town, South Africa.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Collins
authors.affiliation: UCT/MRC Research Unit for Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Alison V
authors.initials: AV
authors.lastname: September
mesh_terms: D000328:Adult; D053674:Aggrecans / Q000235:genetics*; D000070598:Anterior Cruciate Ligament Injuries; D058578:Biglycan / Q000235:genetics*; D016022:Case-Control Studies; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D058575:Decorin / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D024022:Fibrillar Collagens / Q000235:genetics; D000071235:Fibromodulin; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics*; D000071234:Lumican; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics*; D012307:Risk Factors; D012421:Rupture / Q000235:genetics
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; C546884:BGN protein, human; D058578:Biglycan; D011508:Chondroitin Sulfate Proteoglycans; C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D024022:Fibrillar Collagens; C000604306:LUM protein, human; D000071234:Lumican; D011509:Proteoglycans; D000071235:Fibromodulin; D007632:Keratan Sulfate
keywords: ACL; Soft tissue injuries; Sporting injuries