The circulating methylation level of LCK is associated with inflammation of rheumatoid arthritis

Objectives: Lymphocyte-specific protein-tyrosine kinase (LCK) is involved in initiating T cell receptor signaling pathways and is increased in rheumatoid arthritis (RA). Although abnormal expression of LCK in RA has been reported, there was no report to describe the epigenetic especially methylation characteristics of LCK among RA, healthy controls (HCs), and osteoarthritis patients (OAs). Methods: We used targeted methylation sequencing to analyze the methylation level of 7 CpG sites on the promoter region of LCK. Results: We found the overall methylation level of the region was significantly elevated in RA, compared with OAs and HCs. Moreover, the methylation level of all the CpG sites on LCK were significant elevated in RA compared with HC (P= 5.78x10-08 and P=0.02, respectively). The average methylation level of the region was positive correlated with C-reactive protein (CRP, R=0.136, P=0.035) and erythrocyte sedimentation rate (ESR, R=0.187, P=0.0036). The elevated of full methylation haplotype and the decreased of full unmethylation haplotype were contributed to the higher overall methylation level of the region in RA. ROC curve analysis showed that the methylation level of the region on LCK in peripheral blood could be used to distinguish RA group, especially seronegative RA group, from HC and OA group (AUC=0.78). Conclusions: Overall, our study provides the methylation status of the promoter region of LCK and methylation haplotypes patterns in peripheral blood of RA patients, reveal the association between methylation state and the level of inflammation which could enhance our capability in precision medicine of RA.