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Genome-Wide Aggregated Trans Effects Analysis Identifies Genes Encoding Immune Checkpoints as Core Genes for Rheumatoid Arthritis.

Athina Spiliopoulou·Andrii Iakovliev·Darren Plant·Megan Sutcliffe·Seema Sharma·Cankut Cubuk·Myles Lewis·Costantino Pitzalis·Anne Barton·Paul M McKeigue
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Abstract

OBJECTIVE: The sparse effector "omnigenic" hypothesis postulates that the polygenic effects of common single nucleotide polymorphisms (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. METHODS: GATE scores were calculated for 5,400 cases and 453,705 non-cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry. 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, eight 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. Fourteen of these 16 genes are in pathways affecting immunity or inflammation, and six-CD5, CTLA4, TIGIT, LAIR1, TNFRSF14, and PDCD1-encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response. CONCLUSION: These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.

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HumansArthritis, RheumatoidPolymorphism, Single NucleotideGenome-Wide Association StudyAnimalsFemaleMendelian Randomization AnalysisMaleMiceImmune Checkpoint ProteinsGenetic Predisposition to DiseaseReceptors, ImmunologicProgrammed Cell Death 1 ReceptorMiddle AgedJournal ArticleResearch Support, Non-U.S. Gov't

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Athina Spiliopoulou, Andrii Iakovliev, Darren Plant, Megan Sutcliffe, Seema Sharma, Cankut Cubuk, Myles Lewis, Costantino Pitzalis, Anne Barton, Paul M McKeigue. 2025-03-16. Genome-Wide Aggregated Trans Effects Analysis Identifies Genes Encoding Immune Checkpoints as Core Genes for Rheumatoid Arthritis.. https://doi.org/10.1002/art.43125

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