A Genetic Risk Profile in Longitudinal Systemic Lupus Erythematosus (SLE) Cohorts

抽象的。项目4的目标是描绘基因祖先和基因之间复杂的相互作用 环境因素在肾脏受累和器官损害进展速度和严重程度中的作用 系统性红斑狼疮(SLE)。假设SLE患者有更大比例的 非洲人或美洲印第安人的祖先基因单独存在，也与环境因素相结合，包括Low 个人和组级别的SES结构具有更严重和进展更快的SLE，由几个 纵向临床和可溶性生物标记物指数。为了解决这一假设，我们打算(1)使用 建立祖先信息标记(AIMS)，以分别估计个体间的混杂程度 欧洲裔美国人(EA)、非裔美国人(AA)、西班牙裔[来自德克萨斯州(H-TX)、波多黎各(H-PR)和墨西哥 (H-M)]控制混杂因素后有无肾损害和器官损害的SLE患者 因素；(2)确定这些群体中个体混合的估计与 确定肾脏受累和器官损害指数的时间；以及(3)确定个体-和 组级SES结构修改了个体混合体对 系统性红斑狼疮患者肾脏和器官损害的有无、发生时间和严重程度。vbl.使用 符合11项ACR标准中的4项的当前和新登记的SLE患者的扩大资料队列 参与美国大陆、波多黎各和墨西哥的8个学习地点，我们打算利用目标 遗传祖先的独立和联合贡献，使用特征明确的目标和环境(SES) 影响SLE进展速度的因素。汇集的研究人群将代表最大的多种族 到目前为止SLE患者的人口，这将允许对基因和环境进行全面评估 因种族/民族而不同的影响。这种方法提供了快速利用这些资源的最佳机会 并对系统性红斑狼疮的过程和结果提供新的见解。从这个纵向的结果 调查将解决关键问题，以了解环境因素和 可能解释系统性红斑狼疮相关发病率、严重程度和进展的不同趋势的遗传祖先 在非洲和西班牙裔祖先中观察到了这一点。 项目与总体PPG优先级的关系。拟议的研究计划旨在研究 遗传祖先标记与环境因素在疾病进展速度和严重程度上的交互作用 系统性红斑狼疮。该研究计划将(1)最大限度地提高所有四个PPG项目以及行政部门之间的协同效应 和遗传流行病学和生物统计学核心，从而促进对我们声明的特定情况的严格评估 旨在以及时和具有成本效益的方式，(2)加强伙伴机构之间的合作，(3)促进 继续制定有效的风湿病研究计划，(4)加强研究工作 与SLE相关的健康差异和(5)为这一谜团的遗传病因提供了新的见解 自身免疫表型在少数民族人群中不成比例地更频繁和更严重。在……里面 这一能力，这项调查可能被用来最终缩小SLE发病率和死亡率的差距，即 在非洲裔美国人和西班牙裔美国人之间观察到的情况截然不同。

Abstract. The goal of Project 4 is to delineate the complex interactions between genetic ancestry and environmental factors in the rate of progression and severity of renal involvement and organ damage associated with systemic lupus erythematosus (SLE). The hypothesis is that SLE patients with a greater percentage of African or Amerindian ancestry genes both alone and in combination with environmental factors, including low individual- and group-level SES constructs, have more severe and rapidly progressive SLE as defined by several longitudinal clinical and soluble biomarker indices. To address this hypothesis, we intend to (1) use panels of established ancestry informative markers (AIMs) to estimate the extent of individual admixture separately among European American (EA), African American (AA), Hispanic [from Texas (H-TX), Puerto Rico (H-PR) and Mexico (H-M)] SLE patients with and without renal involvement and organ damage after controlling for confounding factors; (2) determine the extent to which the estimates of individual admixture among these groups relate to the time to indices of renal involvement and organ damage; and (3) determine the extent to which individual- and group-level SES constructs modify the effect (additive joint effects and epistasis) of individual admixture on the presence/absence, time to and severity of renal involvement and organ damage among patients with SLE. Using the expanded PROFILE cohort of current and newly enrolled SLE patients meeting 4 of 11 ACR criteria from the participating 8 study sites in the continental US, Puerto Rico and Mexico, we intend to exploit targeted independent and joint contributions of genetic ancestry, using well-characterized AIMs, and environmental (SES) factors with the tempo of SLE progression. The pooled study population will represent the largest multi-ethnic population to date of SLE patients, which will allow for a comprehensive evaluation of gene and environmental influences that are dimorphic by race/ethnicity. This approach offers the best opportunity to rapidly exploit these relationships and to provide novel insight into the course and outcome of SLE. Results from this longitudinal investigation will address key questions for understanding the relative contributions of environmental factors and genetic ancestry that may account for the disparate trends of SLE-related morbidities, severity and progression that is observed among populations of African and Hispanic ancestries. Relationship of Project with Overall PPG Priorities. The proposed research plan is designed to examine the interactions between genetic ancestry markers and environmental factors in the rate of progression and severity of SLE. This research plan will (1) maximize synergy between all four PPG projects as well as the Administrative and Genetic Epidemiology and Biostatistics Cores thereby facilitating a rigorous evaluation of our stated specific aims in a time and cost-effective manner, (2) increase collaboration between partner institutions, (3) foster the continued development of an effective Rheumatic Diseases Research Program, (4) enhance research efforts toward SLE-related health disparities and (5) provide novel insight to the genetic etiology of this enigmatic autoimmune phenotype that is disproportionately more frequent and severe among ethnic minority populations. In this capacity, this investigation may be used to ultimately narrow the gap in SLE morbidity and mortality that is disparately observed between African Americans and Hispanic populations.