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疾病易感性和系统表达 红斑狼疮（SLE）。虽然对导致发病的基因的理解还远未达到 在鉴定40多个易感基因或位点方面取得了重大进展。 然而，对SLE中易患良好预后的遗传因素知之甚少。SLE中的损伤， 定义为疾病活动、治疗干预或合并症导致的不可逆变化 疾病诊断后发生的状况，由系统性研究所开发的仪器测量。 狼疮国际合作诊所作为SLICC/ACR损伤指数。由于男性SLE患者倾向于 在疾病的早期发展损害，这是合理的，性别差异，包括性别 女性中的激素、性染色体连锁基因和/或X染色体失活（XCI）可能起作用 在SLE疾病进展中的作用我们选择了位于X染色体上的雄激素受体基因（AR 并测试了较短的polyGLN多态性（d17）是否赋予较高的雄激素反式激活活性 与SLE的加速损伤有关。我们的初步结果是129名男性和418名女性受影响 1）在疾病的前5年，男性的损害加速，特别是在 发生肾损害; 2）损害增加（SDI e 2）与CAG缩短显著相关 AR的重复长度、较高的累积泼尼松剂量和较长的疾病持续时间。这些数据 表明对睾酮和脱氢表雄酮（DHEA）结合的反应增强， AR中短CAG重复序列的雄激素反式激活活性增强可能是SLE的预后指标 两种性别的伤害。尽管DHEA先前已显示出对治疗SLE表现有益， 最近的研究得出了不一致的结果，突出表明需要进一步研究。我们假设 一个或多个X连锁AR变体易导致SLE中的损害累积，并提出组装一个 > 5，000例临床特征良好的SLE患者（包含> 500例男性患者）的多种族数据集， 解决1）SLE男性是否存在整体或肾损害的风险，2）AR变异有助于识别风险 两种性别的患者的损伤累积，和3）AR反应基因表达的差异水平 有助于SLE的损害。这些研究的结果可能会阐明疾病机制，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， SLE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 (d17) 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 e 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.