Journal
GENOME BIOLOGY
Volume 22, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13059-021-02460-6
Keywords
Functional genomics; Stromal cells; Rheumatoid arthritis; Fibroblast-like synoviocytes
Funding
- Wellcome Trust [207491/Z/17/Z]
- Versus Arthritis [21754, 21348, 21745]
- NIHR Manchester Biomedical Research Centre
- Swiss National Science Foundation [320030_176061]
- Georg and Bertha Schwyzer-Winiker Foundation
- Wellcome Trust [207491/Z/17/Z] Funding Source: Wellcome Trust
- Swiss National Science Foundation (SNF) [320030_176061] Funding Source: Swiss National Science Foundation (SNF)
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The study reveals the potential causal role of fibroblast-like synoviocytes (FLS) in the genetic susceptibility for rheumatoid arthritis (RA), accounting for up to a quarter of RA heritability. Activation of FLS may impact the expression of genes like TNFAIP3 and cellular proliferation.
Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. Results We identify putative causal variants, enhancers, genes, and cell types for 30-60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Conclusion Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.
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