title: Cis- and trans-acting gene regulation is associated with osteoarthritis.
abstract: 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.
authors.affiliation: Institute for Immunology, Rostock, Germany. Electronic address: sandra.mahr@med.uni-rostock.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mahr
authors.affiliation: Charité University Hospital, Medical Faculty, Humboldt University.
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.affiliation: THALES IS, Berlin, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Hilke
authors.affiliation: Contact Software GmbH, Bremen, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Göbel
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
authors.affiliation: Charité University Hospital, Medical Faculty, Humboldt University.
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.affiliation: Orthopedic Surgery, Medical Faculty, University of Rostock, Rostock, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hauschild
authors.affiliation: Institute for Immunology, Rostock, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.affiliation: Charité University Hospital, Medical Faculty, Humboldt University.
authors.forename: Veit
authors.initials: V
authors.lastname: Krenn
authors.affiliation: Orthopädie Zentrum Altona, Hamburg, Germany.
authors.forename: Jasper
authors.initials: J
authors.lastname: Neidel
authors.affiliation: Charité University Hospital, Medical Faculty, Humboldt University.
authors.forename: Carsten
authors.initials: C
authors.lastname: Perka
authors.affiliation: German Rheumatism Research Center, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Institute for Immunology, Rostock, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Thiesen
authors.affiliation: Institute for Immunology, Rostock, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Müller
mesh_terms: D000328:Adult; D000368:Aged; D022981:Allelic Imbalance; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D019902:Chondrocytes / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C452260:NME8 protein, human; C431143:TM2D1 protein, human; D013879:Thioredoxins; D020743:rhoB GTP-Binding Protein