Association of Androgen Receptor Polymorphisms with Damage in SLE

雄激素受体多态性与 SLE 损伤的关联

• 批准号: 9267190
• 负责人: BETTY P TSAO
• 金额: $ 5.37万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267190
• 关键词: Association; Androgen; Receptor; Polymorphisms; Damage

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.

项目摘要 多个基因和环境因素可能导致全身性疾病的敏感性和表达 狼疮红膜（SLE）。虽然对有助于发病机理的基因的理解远 从完整的情况下，在识别40多个易感基因或基因座时取得了重大进展。 然而，关于遗传因素偏见的遗传因素对SLE的良好结果的了解少得多。 SLE的损坏， 由疾病活动，治疗干预措施或联合莫比尔的不可逆变化定义 疾病诊断后发生的疾病是由系统开发的仪器测量的 狼疮国际合作诊所作为SLICC/ACR损害指数。由于男性SLE患者倾向于 在疾病过程中早期发展损害，性别差异包括性别是合理的 恐怖，性染色体连接基因和/或X染色体灭活（XCI）女性可能起作用 在SLE中的疾病进展中。我们选择了位于X染色体上的雄激素受体基因（AR） 并测试了较短的多晶多态性（≤17）​​是否会授予较高的雄激素反式激活活性 我们与SLE的加速损害有关。我们的129名男性和418名女性受影响的初步结果 SLE显示1）在疾病的头5年中，男性加速损害，尤其是有风险 产生肾脏损害，2）与较短的CAG增加损坏（SDI≥2）的显着关联 AR的重复长度，累积性泼尼松剂量和较长的疾病持续时间。这些数据 提出对睾丸激素和脱氢表雄酮（DHEA）结合的反应增强 AR中短CAG重复重复的雄激素反式激活活性增强可能是SLE的预后标记 尽管DHEA以前在治疗SLE表现方面显示出有益的 最近的研究产生了不一致的结果，突出了进一步研究的需求。我们假设这一点 一个或多个X连锁的AR变体易于损害SLE的损害准确性，并提议组装A > 5,000名临床表征良好的SLE患者的多民族数据集，其中包括500名男性患者 解决1）患有SLE的男性是否有整体或肾脏损害的风险，2）AR变体有助于识别危险 性别损害准确性的患者和3）AR反应性基因表达的差异水平 在SLE中造成伤害。这些研究的结果可能会阐明疾病机制，改善 风险评估损害准确性，并促进对选择性雄激素受体调节剂的考虑 SLE的治疗干预措施。