Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression
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. ; 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 Sa¨chsische Aufbaubank–Fo¨rderbank (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), Universita¨t 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.