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

Jana Burkhardt,Holger Kirsten,Elfi Quente,Bernard Prum,Grit Wolfram,Alejandro Balsa,Stefano Bombardieri,Peter Ahnert,Céline Pierlot,Thomas Bardin,Helena Alves,Anke Steiner,Frank Emmrich,Markus Scholz,Pilar Barrera,René Westhovens,Mechthild Blume,Paola Migliorini,Timothy R D J Radstake,Elisabeth Petit‐Teixeira ,Vítor Hugo Teixeira ,François Cornélis

doi:10.1371/journal.pone.0103872

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.

Highlights

Rheumatoid Arthritis (RA) is a chronic inflammatory disease with features of an autoimmune disease [1]
single nucleotide polymorphisms (SNP) rs6136 qualified for genotyping in the European RA family trio set for evaluation of broader relevance
For the genomic position of rs6136 we found an NFKB transcription factor binding sites (TFBS) with the highest possible score in an assay based on chromatin immunoprecipitation (ChIP) followed by genome-wide sequencing in lymphocytes

Summary

Introduction

Rheumatoid Arthritis (RA) is a chronic inflammatory disease with features of an autoimmune disease [1]. One hallmark of RA pathogenesis is infiltration of synovial fluid by autoreactive immune cells These cells release inflammatory cytokines, immunoglobulins, and rheumatoid factor (RF). Macrophages as well as proliferating fibroblast-like cells induce typical joint swelling and pannus formation in the inflamed synovial membrane This cycle of activation and infiltration of inflammatory cells, release of inflammatory mediators and action of aggressive cartilage degrading enzymes causes destruction of cartilage and joints. Adhesion molecules regulate leukocyte circulation, lymphoid cell homing to tissues and inflammatory sites, and transendothelial migration. They participate in lymphocyte co-stimulation, cytotoxicity, lymphohemopoiesis, and B cell apoptosis.

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