Cis- and trans-acting gene regulation is associated with osteoarthritis

Am J Hum Genet. 2006 May;78(5):793-803. doi: 10.1086/503849. Epub 2006 Mar 22.


Osteoarthritis (OA) is a complex disease of the skeleton and is associated with aging. Both environmental and genetic factors contribute to its pathogenesis. We set out to identify novel genes associated with OA, concentrating on regulatory polymorphisms allowing for differential expression. Our strategy to identify differentially expressed genes included an initial transcriptome analysis of the peripheral blood mononuclear cells of six patients with OA and six age-matched healthy controls. These were screened for allelic expression imbalances and potentially regulatory single-nucleotide polymorphisms (SNPs) in the 5' regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. Our approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests, the presence of allelic imbalances confirms cis-regulatory mechanisms for RHOB and TXNDC3. Interestingly, on/off-switching suggests additional trans-regulation for TXNDC3. Moreover, we demonstrate for RHOB and TXNDC3 statistically significant associations between 5' SNPs and the disease that hint at regulatory functions. Investigating the respective genes functionally will not only shed light on the disease association but will also add to the understanding of the pathogenic processes involved in OA and may point out novel therapeutic approaches.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Allelic Imbalance*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Case-Control Studies
  • Chondrocytes / metabolism
  • Cohort Studies
  • Female
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Membrane Proteins
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Oligonucleotide Array Sequence Analysis
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Thioredoxins / genetics
  • Thioredoxins / metabolism
  • Transcription, Genetic*
  • rhoB GTP-Binding Protein / genetics
  • rhoB GTP-Binding Protein / metabolism


  • Carrier Proteins
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • NME8 protein, human
  • TM2D1 protein, human
  • Thioredoxins
  • rhoB GTP-Binding Protein