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 (Nfamiliesâ=â407). 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 (ptotalâ=â0.003). 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 (p1â=â0.004; p2â=â0.0177). 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.
Subject(s)
Alleles , Arthritis, Rheumatoid/genetics , Cell Adhesion/genetics , Gene Expression Regulation , P-Selectin/genetics , Adult , Age of Onset , Binding Sites , Computational Biology , Databases, Genetic , Female , Genetic Association Studies , Genotype , Humans , Male , Polymorphism, Single Nucleotide , Protein Binding , Quantitative Trait Loci , Transcription Factors/metabolism , Young AdultABSTRACT
OBJECTIVE: The functional variant C77G (rs17612648) of PTPRC (CD45) was described to confer risk for systemic sclerosis (SSc) in German Caucasians. We analyzed this association in an independent, larger German cohort. METHODS: We genotyped 171 cases and 179 controls. Cases were subgrouped according to sex, autoantibody profiles, or clinical subsets. RESULTS: No association of SSc with C77G was detected in the whole dataset, in subgroups, or in combined analyses with a previous study. CONCLUSION: The results do not confirm PTPRC C77G as a general and independent risk factor for development of SSc.