Genetic and epigenetic alteration of the programmed cell death 1 in rheumatoid arthritis

Abstract

Background Rheumatoid arthritis (RA) is an autoimmune disease where both genetics and epigenetics are contributing factors. In order to discover genetic and epigenetic associations with RA and its phenotypes, we analysed RNA expression, DNA variations and DNA methylation of programmed cell death 1 (PDCD1) in a cohort of RA patients and healthy controls. Methods RA patients (n = 206) and healthy controls (n = 234) were included for analysis of PDCD1 expression, PDCD1 polymorphisms and PDCD1 methylation. Differences in continuous variables between groups were compared by applying t tests. Associations between phenotypes and genotypes were evaluated with contingency tables. Sensitivity analyses were conducted to confirm the robustness of results, considering potential confounding factors and different treatment response definitions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Results Higher expression of PDCD1 was found in RA compared to controls (P < 0.001), with similar PDCD1 polymorphisms in RA and controls. rs36084323 decreased inadequate response to conventional synthetic disease‐modifying antirheumatic drugs (OR = 0.37, 95% CI = 0.19‐0.72, P = 0.003), and rs41386349 increased rheumatoid factor seropositivity (OR = 11.89, 95% CI = 1.57‐89.87, P = 0.003). Sensitivity analysis adjusting for further potential confounders and using different treatment response definition indicated similar results. Additionally, DNA methylation change at regulatory region of PDCD1 was detected in RA (P = 0.036). Conclusion Altogether, this was the first study to suggest genetic and epigenetic changes of PDCD1 in RA subsets and RA. Independent prospective cohorts are awaited to address the implications of these genetic and epigenetic changes in disease pathogenesis and phenotypes of RA.

Is DNA Methylation a Ray of Sunshine in Predicting Meningioma Prognosis?

“…IGF2BP1, which belongs to the VICKZ family, is an RNA-binding protein that is implicated in tumorigenesis by influencing the translocation and stability of mRNA in some cancers ( 74 ). PDCD1 is a negative regulator of immune responses and likely plays an important role in the progression of many diseases ( 75 ), such as rheumatoid arthritis ( 76 ). Vengoechea et al analyzed 49 samples from three grades of meningiomas and identified nine genes that exhibited the largest absolute difference in methylation intensity.…”

Liquid biopsy in targeting gene polymorphism related to the response within immunocheckpoint inhibitors therapeutic regimen

“…Certain single nucleotide polymorphisms (SNPs) in genes such as PDCD1 (coding for programmed cell death) Rs41386349, this SNP was previously considered as a hot point for Grave's disease and Addison's disease [15], rheumatoid arthritis (RA) [16], Kawasaki disease [17], multiple myeloma [18] and variant A for rs41386349 affects susceptibility of chronic HBV [19]. Whereas, only PD-L1 rs1411262C/T gene polymorphism in the case of Grave's disease and Addison's disease [15], increased rheumatoid factor seropositivity [16] and a higher probability of Kawasaki disease [17] was discovered. The multiple myeloma occurs more often with a PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) variant [18].…”

“…The multiple myeloma occurs more often with a PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) variant [18]. PDCD1 (rs7421861) has been studied in case of esophageal cancer [20] and chronic HBV infection, its oncogenicity [19] as well as RA [16]. PDCD1 gene polymorphisms influence the severity of a disease and are associated with distant metastasis, higher TNM stage, higher PD-1 gene and plasma levels in esophageal cancer patients and risk of esophageal cancer in general [20].…”

Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis

“…RA-associated genetics thoroughly explain neither the heterogeneity of the clinical characteristics nor the treatment differences among patients with RA. In recent years, more and more studies have started to focus on the role of epigenetics in RA ( Ai et al, 2018 ; Guo et al, 2019 , 2020 ; Tseng et al, 2019a ) and investigate the contribution of epigenetics to the heterogeneity of RA. DNA methylation and histone modifications, important epigenetic modifications that affect the expression of immune-related genes and inflammation progression ( Meng et al, 2015 ; Lawrence et al, 2016 ) have become promising mechanisms to explain the pathogenesis of RA ( Mazzone et al, 2019 ).…”