CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in untreated early arthritis: implications for causal gene identification

Nishanthi Thalayasingam, Nisha Nair, Andrew J Skelton, Jonathan Massey, Amy E Anderson, Alexander D Clark, Julie Diboll, Dennis W Lendrem, Louise N. Reynard, Heather J Cordell, Stephen Eyre, John D Isaacs, Anne Barton, Arthur G Pratt

Research output: Contribution to journalArticlepeer-review

Abstract

Objective Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. Seeking insight into genetic risk mechanisms, we conducted an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped early arthritis patients naïve to therapeutic immunomodulation. Methods 344 patients donated RNA and DNA from purified B and/or CD4+ T-cells. Genotyping and global gene expression measurement were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non-HLA RA- SNPs (r2>0.8) were analysed, seeking evidence of cis- or trans- eQTLs according to whether associated probes were or were not within 4MB of these LD blocks. Results Genes subject to cis eQTL effects common to both CD4+ and B-lymphocytes at RA risk loci were FADS1, FADS2, BLK, FCRL3, ORMDL3, PPIL3 and GSDMB. By contrast, those acting on METTL21B, JAZF1, IKZF3, and PADI4 were unique to CD4+ lymphocytes, the latter being identified for the first time in this cell subset. We also found B-lymphocyte-specific eQTLs for SYNGR1 and CD83. At the 8p23 BLK-FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types, the FAM167A effect displaying striking B-lymphocyte specificity. No trans eQTLs approached experiment-wide significance, and linear modelling did not identify a significant influence of biological co-variates upon cis eQTL effect sizes. Conclusion Our findings further refine understanding of candidate causal genes in RA pathogenesis, providing an important platform from which downstream functional studies may be prioritised and directed towards particular cell types.
Original languageEnglish
Pages (from-to)361-370
JournalArthritis and Rheumatology
Volume70
Issue number3
Early online date28 Nov 2017
DOIs
Publication statusPublished - 2018

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