Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

• Published in: European journal of clinical investigation Vol. 52; no. 5; pp. e13715 - n/a
• Main Authors: Tseng, Chia‐Chun, Lin, Yuan‐Zhao, Lin, Chia‐Hui, Hwang, Daw‐Yang, Li, Ruei‐Nian, Tsai, Wen‐Chan, Ou, Tsan‐Teng, Wu, Cheng‐Chin, Lin, Yu‐Chih, Sung, Wan‐Yu, Chen, Kuan‐Yu, Chang, Shun‐Jen, Yen, Jeng‐Hsien
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2022
• Subjects: Arthritis; Arthritis, Rheumatoid - genetics; Autoimmune diseases; bisulphite sequencing; Correlation coefficient; Correlation coefficients; CpG islands; CREM; Cyclic AMP; Cyclic AMP response element modulator; Cyclic AMP Response Element Modulator - genetics; Cyclic AMP Response Element Modulator - metabolism; DNA methylation; Epigenesis, Genetic; Epigenetics; Gene mapping; Genotypes; Humans; Immune system; Inflammation; Linkage disequilibrium; Lymphadenopathy; Methotrexate; Methylation; Phenotypes; Polymerase chain reaction; Quantitative trait loci; Rheumatoid arthritis; Serositis; Serositis - genetics; Transcription; CREM; bisulphite sequencing; rheumatoid arthritis; methylation
• ISSN: 0014-2972; 1365-2362; 1365-2362
• DOI: 10.1111/eci.13715

Background Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune‐mediated inflammatory processes, although it remains unknown whether CREM is involved in RA. Methods This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real‐time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t‐tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression. Results Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001). Conclusions Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology.