CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification. Issue 3 (30th January 2018)

• Record Type: Journal Article
• Authors: Thalayasingam, Nishanthi; Nair, Nisha; Skelton, Andrew J.; Massey, Jonathan; Anderson, Amy E.; Clark, Alexander D.; Diboll, Julie; Lendrem, Dennis W.; Reynard, Louise N.; Cordell, Heather J.; Eyre, Stephen; Isaacs, John D.; Barton, Anne; Pratt, Arthur G.
• Is Part Of: Arthritis & rheumatology. Volume 70:Issue 3(2018)
• Page Start: 361
• Page End: 370
• Publication Date: 2018-01-30
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.40393
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: Rheumatoid 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 r 2 ≥ 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. Results: Genes 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. Conclusion: These 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.