Genotyping in rheumatoid arthritis: a game changer in clinical management?

Pratt, Arthur G.; Isaacs, John D.

doi:10.1586/1744666x.2015.1008454

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…Such molecular insights support a pivotal role for both CD4+ T cell and B cell lineages in the pathogenesis of RA (9)(10)(11). Mapping cellular mechanisms of genetic risk in the disease is far from straightforward, however, because lead single-nucleotide polymorphisms (SNPs) at associated loci are typically noncoding and intergenic, tagging linkage disequilibrium (LD) blocks that contain multiple genes (7,12).…”

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confidence: 99%

THU0003 CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in untreated early arthritis: implications for causal gene identification?

Thalayasingam

Massey²,

Anderson

et al. 2017

Poster Presentations

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BackgroundRheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. Genome-wide association scans (GWAS) have confirmed its association with variants at >100 genetic loci. Outside of the HLA region, accumulating data now highlight an overlap between these risk loci and cell-specific enhancer elements that is maximal in CD4+ lymphocytes, followed by B lymphocytesObjectivesSeeking insight into genetic risk mechanisms, we conducted and compared expression quantitative trait locus (eQTL) analyses of risk loci in CD4+ T cells and B cells from carefully phenotyped early arthritis patients naïve to therapeutic immunomodulation.Methods254 patients donated RNA and DNA from purified B and/or CD4+ T-cells within 4 hours of blood draw. Genotyping and global gene expression measurement were carried out using the Illumina Human CoreExome array and either HT12v4 or WG6v3 BeadChip arrays respectively. Variants in linkage disequilibrium (LD) with 101 confirmed 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.ResultsGenes subject to cis eQTL effects common to both CD4+ and B-lymphocytes at RA risk loci were FADS1, FADS2, BLK, FCRL3, ORMDL3 and GSDMB. At the 8p23 BLK-FAM167A locus, we found adjacent genes subject to eQTLs whose activity differed markedly between cell types, the FAM167A effect displaying striking B-lymphocyte specificity. By contrast, cis eQTLs acting on METTL21B, IKZF3, and PADI4 were unique to CD4+ lymphocytes, the latter two of these being identified for the first time in this cell subset. No trans eQTLs approached experiment-wide significance, and linear modelling did not identify a significant influence of biological co-variates (diagnosis, systemic inflammation, age) upon eQTL effect sizes.ConclusionsOur findings 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.References Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014 Feb 20; 506(7488):376–381. AcknowledgementsWellcome Trust, Academy of Medical Sciences, JGW Patterson Foundation, National Institute of Health Research, Pfizer. Newcastle researchers received infrastructural support via the Arthritis Research UK Centre of Excellence for the RA pathogenesis (RACE). JM and NN are funded by an MRC/Arthritis Research UK stratified medicine award (MR/K015346/1).Disclosure of InterestN. Thalayasingam: None declared, J. Massey: None declared, A. Anderson: None declared, N. Nair: None declared, A. Skelton: None declared, D. Lendrem: None declared, L. Reynard: None declared, H. Cordell: None declared, S. Eyre: None declared, A. Barton: None declared, J. Isaacs: None declared, A. Pratt Grant/research support from: Pfizer

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confidence: 99%

THU0003 CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in untreated early arthritis: implications for causal gene identification?

Thalayasingam

Massey²,

Anderson

et al. 2017

Poster Presentations

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“…Given that TCR only recognizes antigen peptides within HLA molecules on antigen-presenting cells, HLA molecules comprise a very important governing factor for autoimmunity. The HLA gene locus is highly polymorphic and represents the most investigated genetic factor related to RA [21][22][23]. In this context, special attention…”

Section: Introductionmentioning

confidence: 99%

Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

et al. 2021

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Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.

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“…Human leukocyte antigen (HLA) class II molecules are well-studied genetic factors closely associated with RA development (5). However, the contribution of the HLA is considered to only account for 30% of the total genetic factors of susceptibility (6). Thus, it is critical to identify novel biomarkers responsible for RA susceptibility.…”

Section: Introductionmentioning

confidence: 99%

<i>PRKCH</i> polymorphism is associated with rheumatoid arthritis in a Chinese population

Zhuang

Huang

et al. 2019

BST

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Genetic factors have been widely considered to have a substantial effect on the susceptibility to rheumatoid arthritis (RA). The purpose of this study was to determine whether the four newly discovered polymorphisms in a genome-wide association study (GWAS) meta-analysis confer susceptibility to RA in a Chinese Han population. We conducted a case-control study involving 359 RA cases and 873 age-and gender-matched controls and performed genotyping of four single nucleotide polymorphisms (SNPs), rs227163, rs726288, rs3783782 and rs2469434, using the dye terminator-based SNaPshot method. Consequently, we detected significant differences of genotype distribution of rs3783782 in PRKCH between RA and controls. The minor allele frequencies (MAFs) of rs3783782 were significantly higher in RA patients compared to control subjects. Moreover, the rs227163 in TNFRSF9 had higher MAFs in male RA compared with male controls. In addition, the polymorphism of rs3783782 in PRKCH was significantly associated with RA susceptibility (OR = 1.67, 95% CI = 1.32-2.11, p = 1.32 × 10 -5 ). After stratification by gender, the minor (A) allele was strongly associated with increased risk for RA in males (OR = 1.87, 95% CI = 1.34-2.60; p = 1.62 × 10 -4 ) and in females (OR = 1.51, 95% CI = 1.08-2.10; p = 0.014). For rs227163, the minor (C) allele was found to be associated with RA risk only in males (OR = 1.34, 95% CI = 1.02-1.75; p = 0.036). These findings for the first time confirmed that rs3783782 in PRKCH was associated with RA susceptibility in a Chinese population, and rs227163 in TNFRSF9 was associated with RA risk in Chinese males; these SNPs may serve as genetic markers for RA.

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Genotyping in rheumatoid arthritis: a game changer in clinical management?

Cited by 8 publications

References 21 publications

THU0003 CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in untreated early arthritis: implications for causal gene identification?

THU0003 CD4+ and B lymphocyte expression quantitative traits at rheumatoid arthritis risk loci in untreated early arthritis: implications for causal gene identification?

Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

<i>PRKCH</i> polymorphism is associated with rheumatoid arthritis in a Chinese population

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