Association of Androgen Receptor Polymorphisms with Damage in SLE

项目摘要 多个基因和环境因素可能导致系统性疾病的易感性和表达 红斑狼疮(SLE)。虽然对致病基因的了解还远远不够 自完成以来，在识别40多个易感基因或基因座方面取得了重大进展。 然而，人们对导致SLE良好预后的遗传因素知之甚少。系统性红斑狼疮的损害， 由疾病活动、治疗干预或共病引起的不可逆转的变化定义的 疾病诊断后发生的情况，由系统开发的仪器测量 狼疮国际合作临床作为SLICC/ACR损害指数。因为男性SLE患者往往 在疾病的早期发展损害，这是合理的性别差异，包括性别 女性的荷尔蒙、性染色体连锁基因和/或X染色体失活(XCI)可能起作用 在系统性红斑狼疮的疾病进展中。我们选择了位于X染色体上的雄激素受体基因(AR 并测试了较短的多聚谷氨酸多态(≤17)是否具有较高的雄激素反式激活活性 与系统性红斑狼疮的加速损害有关。我们对129名男性和418名女性的初步结果 患有系统性红斑狼疮的患者显示1)在疾病的头5年中，男性的损害加速，尤其是在 发生肾损害，以及2)损害增加的显著关联(sdi≥2)与较短的CAG AR重复长度越大，强的松累积剂量越大，病程越长。这些数据 提示对睾酮和脱氢表雄酮(DHEA)结合的反应增强，由 AR中短CAG重复的雄激素反式激活活性增强可能是SLE的预后标志 对男女都有损害。尽管DHEA此前已显示出在治疗SLE症状方面是有益的， 最近的研究得出了不一致的结果，突显了进一步研究的必要性。我们假设 一个或多个X连锁AR变异体易于在SLE中累积损伤，并建议组装一个 5,000名临床特征良好的SLE患者的多种族数据集，其中包含&gt；500名男性患者 解决1)患有SLE的男性是否存在整体或肾脏损害的风险，2)AR变异有助于识别风险 不同性别患者的损伤累积率，以及3)AR反应基因表达水平的差异 导致系统性红斑狼疮的损害。这些研究的结果可能会阐明疾病的机制，改善 损害累积的风险评估，并促进考虑选择性雄激素受体调节剂 系统性红斑狼疮的治疗干预。

Project Summary Multiple genes and environmental factors likely contribute to disease susceptibility and expression in systemic lupus erythematosus (SLE). While an understanding of the genes that contribute to the pathogenesis is far from complete, significant progress has been made in identifying more than 40 susceptibility genes or loci. However, much less is known about genetic factors predisposing to good outcomes in SLE. Damage in SLE, defined by irreversible changes either as result of disease activity, therapeutic interventions or co-morbid conditions occurring after the disease diagnosis, is measured by an instrument developed by the Systemic Lupus International Collaborating Clinics as the SLICC/ACR damage index. Since male SLE patients tend to develop damage earlier in the course of the illness, it is plausible that gender differences including sex hormones, sex chromosome-linked genes and/or X chromosome inactivation (XCI) in women may play a role in disease progression in SLE. We selected the androgen receptor gene (AR) located on the X chromosome and tested whether shorter polyGLN polymorphisms (≤17) conferring higher androgen transactivation activity were associated with accelerated damage in SLE. Our preliminary results of 129 men and 418 women affected with SLE showed 1) accelerated damage in men during the first 5 years of disease especially in risk for developing renal damage, and 2) significant associations of increased damage (SDI ≥ 2) with shorter CAG repeat length of AR, higher cumulative prednisone dosage, and longer disease duration. These data suggested a heightened response to testosterone and dehydroepiandrosterone (DHEA) binding mediated by enhanced androgen transactivation activity of short CAG repeat in AR might be a prognostic marker for SLE damage in both genders. Although DHEA has previously shown beneficial in treating SLE manifestations, recent studies have yielded inconsistent results, highlighting the need for further studies. We hypothesize that one or more X-linked AR variants predispose to damage accrual in SLE, and propose to assemble a multiethnic dataset of >5,000 clinically well-characterized SLE patients containing > 500 male patients to address whether 1) men with SLE are at risk for overall or renal damage, 2) AR variants help identify at risk patients of both gender for damage accrual, and 3) differential levels of AR responsive gene expression contribute to damage in SLE. Results from these studies are likely to illuminate disease mechanisms, improve risk assessment of damage accrual, and promote consideration of selective androgen receptor modulators in therapeutic interventions of SLE.