CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis

Abstract

ObjectiveRheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation.Methods RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non‐HLA RA single‐nucleotide polymorphisms (defined as r2 ≥ 0.8) were analyzed, seeking evidence of cis‐ or trans‐eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks.ResultsGenes subject to cis‐eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1,FADS2,BLK,FCRL3,ORMDL3,PPIL3, and GSDMB. In contrast, those acting on METTL21B,JAZF1,IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte–specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK–FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans‐eQTLs approached experiment‐wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis‐eQTL effect sizes.ConclusionThese findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.

The CD83 Molecule – An Important Immune Checkpoint

“…Understanding the effects of specific immune modulating interventions can elucidate definitive molecular or cellular checkpoints of the complex inflammatory networks which modulate autoimmune diseases. Given the important role of CD83 for immune responses to non-self, it is not surprising that there are several reports of CD83 being involved in autoimmune processes (38,39,55,(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110). A recent report summarized immune-modulating functions of sCD83 therapy in models of multiple sclerosis, autoimmune uveitis and systemic lupus erythematosus (3).…”

“…Importantly, this expression of sCD83 in early stage RA patients was unaffected by anti-TNF-α treatment (106). Moreover, CD83 (e.g., in B lymphocytes) possesses different regulatory functions of disease risk variants in RA (107,108). Interference with autoimmunemediated cytokine production is a poorly developed approach to treat autoimmune and inflammatory diseases, such as RA.…”

Using functional genomics to advance the understanding of psoriatic arthritis

“…Because eQTLs are context specific, some studies have used cells derived from patients to discover specific links with disease associated loci. For example, Thalayasingam et al mapped eQTLs in CD4+ T cells and B cells from 344 patients with untreated RA identifying a number of candidate genes linked to variants associated with RA [ 45 ]. In PsA, Bowes et al mapped their novel disease associated loci using cell-type specific eQTLs from CD4+ and CD8+ primary T cells [ 19 ].…”

Identification of rheumatoid arthritis causal genes using functional genomics

“…Taken to its extremity, this approach of focussing on ever more tightly defined cell types and conditions has led to the identification of eQTLs using single‐cell RNA sequencing (scRNA‐seq) of peripheral blood mononuclear cells . Ultimately, the most relevant collection may be carefully defined cell types of known clinical relevance isolated from patient samples, as performed on T helper cells and B cells isolated from patients with RA …”