Department of Internal Medicine, Section of Endocrinology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
Arthritis Res Ther. 2010;12(4):R159. doi: 10.1186/ar3118. Epub 2010 Aug 21.
The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.
The presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined.
Carriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9β minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNFα) therapy (P < 0.05).
The minor alleles of the 9β and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa.
糖皮质激素受体 (GR) 在免疫系统中发挥重要的调节作用。GR 基因的四个多态性与糖皮质激素 (GC) 敏感性的差异相关；多态性 N363 S 和 BclI 的次要等位基因与 GC 相对超敏性相关，而 ER22/23EK 和 9β 的多态性与相对 GC 抵抗相关。由于 GC 敏感性的差异可能影响免疫效应功能，我们研究了这些多态性是否与类风湿关节炎 (RA) 的易感性和 RA 疾病严重程度相关。
在健康对照组（n=5033）和 RA 患者（n=368）中评估 GR 多态性的存在。第二个对照组（n=532）用于结果确认。在 RA 患者中，研究了 GR 多态性与疾病严重程度的关系。
携带 N363 S 和 BclI 次要等位基因的个体患 RA 的风险较低：比值比 (OR) 分别为 0.55（95%置信区间 (CI) 0.32-0.96，P=0.032）和 0.73（95%CI 0.58-0.91，P=0.006）。相比之下，携带 9β 次要等位基因的个体患 RA 的风险更高：OR=1.26（95%CI 1.00-1.60，P=0.050）。对于 ER22/23EK 次要等位基因携带者，发现风险增加的趋势 OR=1.42（95%CI 0.95-2.13，P=0.086）。所有 ER22/23EK 携带者（32/32）均有侵蚀性疾病，而非携带者仅有 77%（259/336）有（P=0.008）。此外，ER22/23EK 携带者更频繁地接受抗肿瘤坏死因子-α (TNFα) 治疗（P<0.05）。
9β 和 ER22/23EK 多态性的次要等位基因似乎与 RA 发病倾向增加相关。相反，N363 S 和 BclI 多态性的次要等位基因与 RA 发病倾向降低相关。这些相反的关联表明，GC 抵抗的固有决定因素可能易导致自身免疫，至少在 RA 中如此，反之亦然。
