Toonen Erik J M, Barrera Pilar, Fransen Jaap, de Brouwer Arjan P M, Eijsbouts Agnes M, Miossec Pierre, Marotte Hubert, Scheffer Hans, van Riel Piet L C M, Franke Barbara, Coenen Marieke J H
Arthritis Res Ther. 2012 Dec 7;14(6):R264. doi: 10.1186/ar4110.
The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).
A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.
Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.
Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.
本研究的目的是调查肿瘤坏死因子α（TNFA）基因-308G>A启动子多态性是否与一大群类风湿关节炎（RA）患者的疾病严重程度和放射学关节损伤相关。
对一个长期观察性早期RA起始队列（n = 208）进行TNFA -308G>A启动子多态性（rs1800629）基因分型，该队列具有疾病3年、6年和9年后疾病活动和放射学损伤的详细信息。进行纵向回归分析以评估基因型对RA疾病严重程度和关节损伤的影响。随后，进行荟萃分析，纳入所有公开可用的数据，以进一步检验关节侵蚀与TNFA多态性之间的关联。为了更多地了解多态性作用背后的机制，使用从RA患者外周血中分离的RNA（n = 66）通过定量PCR进行TNFA基因表达分析。
校正性别和疾病活动后的纵向回归分析显示，GG基因型组与GA+AA基因型组在总关节损伤方面存在显著差异（P = 0.002），且随时间稳定。纳入2053例患者的荟萃分析证实该基因变异与侵蚀的发生相关（优势比0.78，95%可信区间0.62，0.98）。不同基因型的TNFA基因表达未观察到显著差异，这证实了先前在健康个体中的发现。
我们的数据证实TNFA基因-308G>A启动子多态性与RA患者的关节损伤相关。这不是由基因型之间TNFA基因表达的差异介导的。
