Abstract: Rheumatoid Arthritis-associated Interstitial Lung Disease (RA-ILD) significantly reduces life quality and survival, necessitating improvements in its understanding and clinical management. We addressed these goals using DNA methylation analysis, which has not been done in RA-ILD samples, by comparing 32 RA patients with ILD diagnosed less than one year before (cases) and 32 matched RA patients without ILD (controls). This analysis identified 6679 differentially methylated positions (DMPs) with ?? ? 2% and FDR < 0.05, and 576 differentially methylated regions in RA-ILD. Some DMPs were near mucin, collagen, and telomere maintenance genes. Also, the most notably enriched gene set (up to padj = 1.9 × 10?38) included genes overexpressed in fibrosis by monocytes and alveolar macrophages. Other significantly enriched gene sets, known to be dysregulated in fibrosis, included the mitotic spindle and the Rho GTPases. Additionally, analysis of transcription factor binding sites around DMPs showed unique enrichment near the liver X receptor element (LXRE), which is associated with fibrosis in multiple tissues. These results were consistent and unaffected by stricter significance thresholds. They indicated that differential DNA methylation may serve as blood biomarkers for RA-ILD including some related to lung fibrosis pathways.

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