Association of Androgen Receptor Polymorphisms with Damage in SLE

描述(申请人提供)：多个基因和环境因素可能导致系统性红斑狼疮(SLE)的疾病易感性和表达。虽然对致病基因的了解还远未完成，但在识别40多个易感基因或基因座方面已经取得了重大进展。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、治疗干预或疾病诊断后发生的共病条件造成的不可逆转的变化来定义，由系统性红斑狼疮国际合作诊所开发的一种仪器作为SLICC/ACR损害指数来衡量。由于男性SLE患者往往在病程较早时出现损害，因此，性别差异，包括女性的性激素、性染色体相关基因和/或X染色体失活(XCI)，可能在SLE的疾病进展中发挥作用。我们选择了位于X染色体上的雄激素受体基因(AR)，并测试了具有较高雄激素反式激活活性的较短多聚谷氨酸多态(D17)是否与SLE的加速损伤有关。我们对129名男性和418名女性SLE患者的初步结果表明：1)男性在疾病的前5年加速损害，特别是在发生肾损害的风险方面，以及2)损害增加(SDIe2)与AR的CAG重复长度较短、泼尼松累积剂量较高和病程较长显著相关。这些数据表明，AR中短CAG重复序列的雄激素反式激活活性增强所介导的对睾酮和脱氢表雄酮(DHEA)结合的反应增强可能是男女SLE损害的预后标志。尽管DHEA之前已经显示出对治疗SLE症状有好处，但最近的研究得出了不一致的结果，突出了进一步研究的必要性。我们假设一个或多个X连锁AR变种易导致系统性红斑狼疮的损害，并建议收集5,000名临床特征良好的系统性红斑狼疮患者的多种族数据集，其中包括500名男性患者，以确定是否1)患有SLE的男性有整体或肾脏损害的风险，2)AR变异体有助于识别高危患者 损伤累加的性别和3)AR反应基因表达的不同水平对SLE的损伤有贡献。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，并促进选择性雄激素受体调节剂在SLE治疗干预中的考虑。

DESCRIPTION (provided by applicant): 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.