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- Title
CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis.
- 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.
- 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 r2 ≥ 0.8) were analyzed, seeking evidence of <italic>cis</italic>‐ or <italic>trans</italic>‐eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks. Results: Genes subject to <italic>cis</italic>‐eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were <italic>FADS1</italic>,<italic> FADS2</italic>,<italic> BLK</italic>,<italic> FCRL3</italic>,<italic> ORMDL3</italic>,<italic> PPIL3</italic>, and <italic>GSDMB</italic>. In contrast, those acting on <italic>METTL21B</italic>,<italic> JAZF1</italic>,<italic> IKZF3,</italic> and <italic>PADI4</italic> 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 <italic>SYNGR1</italic> and <italic>CD83</italic> were also found. At the 8p23 <italic>BLK–FAM167A</italic> locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the <italic>FAM167A</italic> effect displayed striking B lymphocyte specificity. No <italic>trans</italic>‐eQTLs approached experiment‐wide significance, and linear modeling did not identify a significant influence of biologic covariates on <italic>cis</italic>‐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.
- Subjects
GENETICS of rheumatoid arthritis; RHEUMATOID arthritis risk factors; ARTHRITIS; B cells; GENE expression; GENETIC techniques; T cells; BIOCHIPS; DISEASE complications
- Publication
Arthritis & Rheumatology, 2018, Vol 70, Issue 3, p361
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.40393