Eunji Ha¹, So-Young Bang^2,3, Jiwoo Lim¹, Jun Ho Yun⁴, Jeong-Min Kim⁴, Jae-Bum Bae⁴, Hye-Soon Lee^2,3, Bong-Jo Kim⁴, Kwangwoo Kim¹, Sang-Cheol Bae^2,3

¹Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea
²Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
³Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
⁴Division of Genome Science, Department of Precision Medicine, National Institute of Health, Osong Health Technology Administration Complex, Cheongju, Republic of Korea

EH and S-YB contributed equally.

Correspondence to Professor Sang-Cheol Bae, Professor Kwangwoo Kim, Dr Bong-Jo Kim.

Objective CD4⁺ T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4⁺ T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape.

Methods We profiled genome-wide variants, gene expression and DNA methylation in CD4⁺ T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics.

Results A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA.

Conclusion Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4⁺ T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.