| Title: | Genome-wide aggregated trans- effects analysis identifies genes encoding immune checkpoints as core genes for rheumatoid arthritis |
| Journal: | Arthritis & Rheumatology |
| Published: | 29 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39887658/ |
| DOI: | https://doi.org/10.1002/art.43125 |
Publication 14473
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Abstract
OBJECTIVES: The sparse effector "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated by trans- effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome-wide aggregated trans- effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels.</p>
METHODS: GATE scores were calculated for 5400 cases and 453705 non-cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry.</p>
RESULTS: Testing for association with GATE scores identified 16 putative core genes for rheumatoid arthritis outside the HLA region, of which six - TP53BP1, PDCD1, TNFRSF14, LAIR1, LILRA4, and IDO1 - were supported by Mendelian randomization analysis based on the marginal likelihood of the causal effect parameter. Five of these 16 genes were validated by a reported association of rheumatoid arthritis with SNPs within 200 kb of the transcription site, 8 by association of the measured protein level with rheumatoid arthritis in UK Biobank, 10 by experimental perturbation in mouse models of inflammatory arthritis, and two - CTLA4 and PDCD1 - by evidence that drugs targeting the gene cause or ameliorate inflammatory arthritis in humans. 14 of these 16 genes are in pathways affecting immunity or inflammation and six - CD5, CTLA4, TIGIT, LAIR1, TNFRSF14, PDCD1 - encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response.</p>
CONCLUSION: These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.</p>
10 Authors
- Athina Spiliopoulou
- Andrii Iakovliev
- Darren Plant
- Megan Sutcliffe
- Seema Sharma
- Cankut Cubuk
- Myles Lewis
- Costantino Pitzalis
- Anne Barton
- Paul M McKeigue
1 Application
| Application ID | Title |
|---|---|
| 23652 | Understanding the Genetics of Type 1 Diabetes and Related Complications |
Enabling scientific discoveries that improve human health