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CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

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 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.

SUBMITTER: Thalayasingam N

PROVIDER: S-EPMC5888199 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

Thalayasingam Nishanthi N Nair Nisha N Skelton Andrew J AJ Massey Jonathan J Anderson Amy E AE Clark Alexander D AD Diboll Julie J Lendrem Dennis W DW Reynard Louise N LN Cordell Heather J HJ Eyre Stephen S Isaacs John D JD Barton Anne A Pratt Arthur G AG

Arthritis & rheumatology (Hoboken, N.J.) 20180130 3

<h4>Objective</h4>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.<h4>Methods</h4>RNA and DNA were isolated from purified B and/or CD4+ T cells obtained ...[more]

PMID: 29193869

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Project description:Rheumatoid arthritis (RA) is influenced by oral and gut bacteria; however, much less is known about the relationship between oral or gut viromes and RA. Here, we performed whole-oral- and whole-gut-virome analyses based on shotgun sequencing of 497 samples. A comparative analysis of the oral and gut viromes in healthy controls and untreated and treated RA patients was performed, and system interaction networks among viruses, bacteria, and RA-associated clinical indices were constructed to address the potential relationship between the virome and RA by principal-coordinate analysis, distance-based redundancy analysis, permutational multivariate analysis, Spearman correlation coefficient analysis, and random-forest model analysis. The results showed that the viromes could be profiled in dental plaque, saliva, and fecal samples, among which saliva had the highest within-sample diversity. Importantly, significantly different diversities and compositions of the oral (i.e., dental plaque and saliva) viromes were observed not only between RA patients and healthy controls but also between untreated and treated RA patients, yet there were relatively minor differences in the gut viromes. Furthermore, to understand how these viruses affected the bacteriome, a virus-bacterium interaction network was constructed from dental plaque, saliva, and fecal samples of RA patients. Additionally, some RA-associated oral taxa, including Lactococcus phage (vOTU70), Bacteroides vulgatus, Lactococcus lactis, Escherichia coli, and Neisseria elongata, were correlated with the RA-related clinical indices. Whole-virome analysis illustrated the potential role of the oral and gut viromes in affecting our body either directly or via bacteria, which characterized neglected and new candidates contributing to the development of RA. IMPORTANCE Our results demonstrated community variation among dental plaque, saliva, and fecal viromes. In oral and gut samples from untreated and treated RA patients, the perturbance of viral composition and the correlation network of microbes and RA-associated clinical indices might be involved in the pathogenicity of RA. The findings in this study expand the knowledge of the potential role of oral and gut viral communities in the development of RA and may contribute to research on correlations between viruses and other diseases.

Dataset Information

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

Publications

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

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