Wagener Frank A D T G, Toonen Erik J M, Wigman Lonneke, Fransen Jaap, Creemers Marjonne C W, Radstake Timothy R D J, Coenen Marieke J H, Barrera Pilar, van Riel Piet L C M, Russel Frans G M
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Arthritis Rheum. 2008 Nov;58(11):3388-93. doi: 10.1002/art.23970.
The guanine-thymidine (GT)n repeat in the HMOX1 promoter determines the level of induction of the heme-degrading enzyme heme oxygenase 1 (HO-1), which protects against inflammatory and oxidative stress. In individuals with short (GT)n repeats (where n < 25; SS genotype), higher levels of HO-1 activity are induced more rapidly than in those with long (GT)n repeats (where n > or = 25; LL genotype). Recently, it was demonstrated that HO-1 activity protects against the onset of rheumatoid arthritis (RA). The aim of this study was to determine whether the (GT)n-repeat length within the HMOX1 promoter region is associated with RA disease severity and radiographic joint damage.
A cohort of 325 well-characterized RA patients and 273 controls was investigated by DNA fragment-length analysis for the association of (GT)n repeats in the HMOX1 promoter region with RA disease susceptibility and severity.
Although no significant differences in genotype or allele frequency were found between controls and RA patients, the odds ratios corresponded well to those in the previously described cohort. Among patients, those carrying the SS genotype had a more favorable radiographic outcome over 9 years than those carrying the LL genotype. This was unexpected since no differences in disease activity were found between the genotypes or alleles.
Patients with the SS genotype have a better long-term radiographic outcome despite poor prognostic markers at baseline and despite disease activity at followup similar to that of patients with the LL genotype. This suggests that the HMOX1/HO-1 system is involved in the uncoupling of disease activity and joint damage and may provide a novel target for the treatment of RA.
HMOX1启动子中的鸟嘌呤 - 胸腺嘧啶（GT）n重复序列决定了血红素降解酶血红素加氧酶1（HO - 1）的诱导水平，该酶可抵御炎症和氧化应激。在（GT）n重复序列较短（n < 25；SS基因型）的个体中，HO - 1活性水平的诱导比（GT）n重复序列较长（n≥25；LL基因型）的个体更快。最近有研究表明，HO - 1活性可预防类风湿性关节炎（RA）的发病。本研究的目的是确定HMOX1启动子区域内的（GT）n重复序列长度是否与RA疾病严重程度和影像学关节损伤相关。
通过DNA片段长度分析，对325例特征明确的RA患者和273例对照进行研究，以探讨HMOX1启动子区域（GT）n重复序列与RA疾病易感性和严重程度的关系。
虽然在对照组和RA患者之间未发现基因型或等位基因频率的显著差异，但优势比与先前描述的队列中的结果相符。在患者中，携带SS基因型的患者在9年中的影像学结果比携带LL基因型的患者更有利。这出乎意料，因为在基因型或等位基因之间未发现疾病活动度的差异。
尽管基线时预后标志物较差且随访时疾病活动度与LL基因型患者相似，但SS基因型患者的长期影像学结果更好。这表明HMOX1/HO - 1系统参与了疾病活动度与关节损伤的解偶联，可能为RA治疗提供新靶点。
