Background/Purpose: Small RNAs (sRNAs) are important gene regulators and markers of disease. Transfer RNA (tRNA)-derived sRNAs (tDRs), including tRNA fragments (tRFs) and halves (tRHs), are novel regulatory sRNAs, which are often upregulated in the setting of cellular stress to downregulate metabolic processes. Rheumatoid arthritis (RA), a common autoimmune disease, is associated with excessive cellular stress due to immune activation. We hypothesized that circulating tDRs are altered in patients with RA and serve as novel markers for RA and RA disease activity.

Methods: Plasma sRNA sequencing was performed on archived samples from 167 RA patients, and 91 matched controls using Illumina NextSeq500. tDRs were quantified by TIGER pipeline, permitting one mismatch. Total tDRs, individual tDRs and tDRs based on amino acid of the parent tRNA normalized to total reads were compared between RA and control subjects by DESeq2 with adjustment for age, race, sex, and batch with 5% false discovery rate and multiple test correction.

Results: RA patients had 1.16-fold higher proportion of plasma tDRs compared to controls (P=0.04). Among RA patients a higher proportion of total plasma tDR reads was associated with higher disease activity by DAS28 score (rho=0.17, p=0.03), erythrocyte sedimentation rate (rho=0.21, p=0.007) and swollen joint count (rho=0.18, p=0.02). Several individual tDR sequences were increased (3.7-fold to 1.5-fold), while one individual tDR sequence was decreased 2.2-fold among RA patients. tDRs aligning to a suppressor tRNA were increased 1.7-fold, while tDRs aligning to tRNAs encoding for asparagine, isoleucine, and aspartic acid were decreased (1.8-fold to 1.5-fold) among RA patients.

Conclusion: RA patients have a greater proportion of plasma tDRs compared to controls, and total tDRs were correlated with disease activity. Several individual tDRs and tDRs aligning to a suppressor tRNA and several other amino acid encoding tRNAs were altered in RA patients. Circulating tDRs may be novel markers of RA diagnosis and disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-transfer-rna-derived-small-rnas-are-altered-in-patients-with-rheumatoid-arthritis/