title: Allelic expression analysis of the osteoarthritis susceptibility gene COL11A1 in human joint tissues.
abstract: BACKGROUND
  The single nucleotide polymorphism (SNP) rs2615977 is associated with osteoarthritis (OA) and is located in intron 31 of COL11A1, a strong candidate gene for this degenerative musculoskeletal disease. Furthermore, the common non-synonymous COL11A1 SNP rs1676486 is associated with another degenerative musculoskeletal disease, lumbar disc herniation (LDH). rs1676486 is a C-T transition mediating its affect on LDH susceptibility by modulating COL11A1 expression. The risk T-allele of rs1676486 leads to reduced expression of the COL11A1 transcript, a phenomenon known as allelic expression imbalance (AEI). We were keen therefore to assess whether the effect that rs1676486 has on COL11A1 expression in LDH is also observed in OA and whether the rs2615977 association to OA also marked AEI.
  
  
  METHODS
  Using RNA from OA cartilage, we assessed whether either SNP correlated with COL11A1 AEI by 1) measuring COL11A1 expression and stratifying the data by genotype at each SNP; and 2) quantifying the mRNA transcribed from each allele of the two SNPs. We also assessed whether rs1676486 was associated with OA susceptibility using a case-control cohort of over 18,000 individuals.
  
  
  RESULTS
  We observed significant AEI at rs1676486 (p < 0.0001) with the T-allele correlating with reduced COL11A1 expression. This corresponded with observations in LDH but the SNP was not associated with OA. We did not observe AEI at rs2615977.
  
  
  CONCLUSIONS
  COL11A1 is subject to AEI in OA cartilage. AEI at rs1676486 is a risk factor for LDH, but not for OA. These two diseases therefore share a common functional phenotype, namely AEI of COL11A1, but this appears to be a disease risk only in LDH. Other functional effects on COL11A1 presumably account for the OA susceptibility that maps to this gene.
authors.affiliation: Newcastle University, Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Emma V A
authors.initials: EV
authors.lastname: Raine
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Dodd
authors.forename: Louise N
authors.initials: LN
authors.lastname: Reynard
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
mesh_terms: D022981:Allelic Imbalance; D002358:Cartilage, Articular / Q000737:chemistry*; D016022:Case-Control Studies; D024161:Collagen Type XI / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006621:Hip Joint / Q000737:chemistry*; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000235:genetics; D007438:Introns; D007719:Knee Joint / Q000737:chemistry*; D015207:Osteoarthritis, Hip / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis*; D012307:Risk Factors
chemical_list: C574182:COL11A1 protein, human; D024161:Collagen Type XI; D012333:RNA, Messenger