title: Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression.
abstract: In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p<10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Burkhardt
authors.affiliation: University Leipzig, Institute for Clinical Immunology and Tranfusion Medicine (IKIT), Universität Leipzig, Leipzig, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Blume
authors.affiliation: Genhotel-EA 3886, Université d'Evry-Val d'Essonne, Evry, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petit-Teixeira
authors.affiliation: Centre for Respiratory Research, University College London, London, United Kingdom.
authors.forename: Vitor
authors.initials: V
authors.lastname: Hugo Teixeira
authors.affiliation: University Leipzig, Institute for Clinical Immunology and Tranfusion Medicine (IKIT), Universität Leipzig, Leipzig, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Steiner
authors.affiliation: Fraunhofer Institute for Celltherapy and Immunology (IZI), Leipzig, Germany.
authors.forename: Elfi
authors.initials: E
authors.lastname: Quente
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Wolfram
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: Genhotel-EA 3886, Université d'Evry-Val d'Essonne, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Pierlot
authors.affiliation: Pisa University, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Migliorini
authors.affiliation: Pisa University, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bombardieri
authors.affiliation: La Paz Hospital, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.affiliation: Rheumatology KU Leuven, Leuven, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.affiliation: Nijmegen University, Nijmegen, the Netherlands.
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.affiliation: University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.affiliation: Porto San Joao Hospital, Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Alves
authors.affiliation: Fédération de Rhumatologie, Lariboisière Hospital, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bardin
authors.affiliation: Laboratoire Statistique & Génome, Université d'Evry-Val d'Essonne, Evry, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Prum
authors.affiliation: Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, Leipzig, Germany; University Leipzig, Institute for Clinical Immunology and Tranfusion Medicine (IKIT), Universität Leipzig, Leipzig, Germany; Fraunhofer Institute for Celltherapy and Immunology (IZI), Leipzig, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Emmrich
authors.affiliation: GenHotel-Auvergne, Université d'Auvergne, Clermont-Ferrand, France.
authors.forename: François
authors.initials: F
authors.lastname: Cornelis
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ahnert
authors.affiliation: Fraunhofer Institute for Celltherapy and Immunology (IZI), Leipzig, Germany; LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001665:Binding Sites; D002448:Cell Adhesion / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D019007:P-Selectin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D019007:P-Selectin; C546937:SELP protein, human; D014157:Transcription Factors