Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression

PLoS One. 2014 Aug 22;9(8):e103872. doi: 10.1371/journal.pone.0103872. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Alleles*
  • Arthritis, Rheumatoid / genetics*
  • Binding Sites
  • Cell Adhesion / genetics*
  • Computational Biology
  • Databases, Genetic
  • Female
  • Gene Expression Regulation*
  • Genetic Association Studies
  • Genotype
  • Humans
  • Male
  • P-Selectin / genetics*
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Quantitative Trait Loci
  • Transcription Factors / metabolism
  • Young Adult

Substances

  • P-Selectin
  • SELP protein, human
  • Transcription Factors

Grants and funding

The work presented in this paper was made possible by funding from the German Federal Ministry of Education and Research (BMBF, PtJ-Bio, 1315883, www.bmbf.de). This project was also supported by grant no. 7692/1187 from the Sächsische Aufbaubank–Förderbank (www.sab.sachsen.de), by grant no. 4212/04-04 from the European Fund for Regional Development (EFRE, ec.europa.eu), by the German Federal Ministry for Education and Research (Hochschul- und Wissenschaftsprogramm; “Kompetenznetz Rheuma” 01GI9949 to IM), by the Rosa-Luxemburg-Stiftung (www.rosalux.de) and by the Foundation for Science and Technology, Portugal (grant SFRH/BD/23304/2005, www.fct.pt). PA, MS and HK were also supported by LIFE – Leipzig Research Center for Civilization Diseases (life.uni-leipzig.de), Universität Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.