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To investigate the associations of DNA methylation levels and mRNA expressions of DNA cytosine-5-methyltransferase 1 (DNMT1) and methyl CpG-binding domain 2 (MBD2) with rheumatoid arthritis (RA).The global methylation status of DNA was measured in 65 patients with RA and 64 healthy controls by the ELISA method. DNMT1 and MBD2 mRNA were also detected in 177 RA patients and 95 controls using the quantitative real-time polymerase chain reaction method.The global methylation of DNA was significantly decreased in the RA patients compared to the controls (p=0.005, 95% CI=0.0835-0.4503). The patients with RA had higher expressions of DNMT1 and MBD2 mRNA than the controls (p0.001, 95% CI=-0.0024 to -0.0053 and p0.001, 95% CI=-0.0079 to -0.0167, respectively). We also found that the MBD2 mRNA level was not related to the disease activity of RA. However, the expression of DNMT1 mRNA tended to be associated with the disease activity of RA (p=0.08). The levels of DNA methylation and DNMT1 mRNA were significantly decreased in the patients with anti-CCP antibody compared with those without (p=0.005, 95% CI=-0.7333 to -0.1373 and p=0.003, 95% CI=-0.0071 to -0.0022, respectively). The differences in the methylation level and expressions of DNMT1 and MBD2 were not significant between the patients treated with and without anti-TNFα biological agents (Enbrel or Humira).This study demonstrated that the RA patients have a significantly lower level of DNA methylation than the controls. Moreover, RA patients have higher expressions of DNMT1 and MBD2 mRNA. The anti-TNFα biological agents do not seem to affect DNA methylation and mRNA expressions of DNMT1 and MBD2 in RA patients.

Objectives To investigate the role of inhibitor of kB-like ( IkBL ) gene polymorphisms in the pathogenesis of rheumatoid arthritis (RA) in Taiwan. Methods One hundred and twenty-nine patients with RA and 110 healthy controls were enrolled in this study. Polymerase chain reaction (PCR)/direct sequencing was used to determine the polymorphisms of IkBL −421 8T/9T, −324 C/G, −262 A/G, and −62 A/T. PCR/restriction fragment length polymorphism was used to determine the IkBL +738 T/C polymorphisms. Results The genotype distribution of IkBL −421 was significantly different between DR4 (+) RA patients and DR4 (+) controls ( p = 0.02). The allele frequency of IkBL −421 8T was significantly higher in DR4 (+) RA patients than in DR4 (+) controls ( p = 0.004, OR = 7.2, 95% CI = 1.7–29.2). The allele carriage frequency of IkBL −421 8T also tended to be increased in DR4 (+) RA patients in comparison with DR4(+) controls ( p = 0.07, OR = 14.6, 95% CI = 1.4–147.0). We also found that the allele frequency of IkBL −62 T was significantly higher in RA patients than in controls ( p = 0.04, OR = 1.5, 95% CI = 1.1–2.1). The allele carriage frequency of IkBL −62 T tended to be increased in RA patients ( p = 0.08, OR = 1.7, 95% CI = 1.0–3.0). The estimated haplotype frequency of IkBL −421 8T/−62 T tended to be increased in RA patients compared with controls ( p = 0.07, OR = 1.4, 95% CI = 1.0–2.0). Conclusion The IkBL −62 T may be associated with the development of RA in Taiwan. The IkBL −421 8T may also be related to susceptibility to RA in HLA-DR4 (+) individuals. This study shows that the estimated haplotype IkBL −421 8T/−62 T tends to be associated with susceptibility to RA in Taiwan.

Objectives: To investigate the association of tumor necrosis factor (TNF) microsatellite alleles with the pathogenesis of rheumatoid arthritis (RA) in Taiwan. Methods: The TNF a, b, c, d, and e microsatellites were determined in 112 patients with RA and 99 healthy controls by using polymerase chain reaction (PCR) and electrophoresis with sequencing gel. All of these patients and controls had known HLA-DR genotypes and TNF-308 polymorphisms. Results: The phenotypic frequency of TNFa9 was significantly higher in DR4(−) RA patients than in DR4(−) controls. However, the phenotypic frequency of TNFb6 was significantly higher in RA patients than in controls in the presence of HLA-DR4. The phenotypic frequency of TNFa3-e1 was significantly lower in DR4(+) RA patients than in DR4(+) controls, while a negative linkage disequilibrium was noted between TNFa3-e1 and HLA-DR4. TNF microsatellite alleles were not related to the prevalences of bone erosion, rheumatoid nodule, sicca syndrome, pulmonary fibrosis, and seropositivity of rheumatoid factor (RF) in patients with RA. Conclusion: The associations of TNF microsatellites with the susceptibility to RA in Taiwan are not completely independent of the HLA-DR associations. The association of TNFb6 with the susceptibility to RA depends on the presence of HLA-DR4, and the correlation of TNFa9 to RA depends on the absence of HLA-DR4. The negative association of TNFa3-e1 with RA may be secondary to the negative linkage disequilibrium between TNFa3-e1 and HLA-DR4. Moreover, TNFb6 and HLA-DR4 have a synergistic effect on the susceptibility to RA. TNFa3-e1 and TNF-308A have a synergistic effect on preventing from RA. The TNF microsatellite alleles are not related to the clinical manifestations and severity of RA patients in Taiwan.

The uncommon allele (TNF2) of a polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene has been reported to be increased in Caucasian systemic lupus erythematosus (SLE) patients (associated with HLA-DR3). To investigate whether TNF2 contributes towards susceptibility to Chinese SLE patients (not associated with HLA-DR3), 100 patients with SLE and 107 controls were studied. The frequency of TNF2 allele in controls was 0.140. There was a strong association between TNF2 allele and HLA-DR3 (P10(-8)) in controls. The frequency of TNF2 allele in SLE patients was 0.15. There was no difference in frequencies of TNF2 allele between patients and controls. This finding strongly suggests that TNF2 does not play a direct role in the susceptibility of SLE.