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

抽象的。项目4的目标是描述遗传祖先和 环境因素对肾脏受累和相关器官损害的进展率和严重程度的影响 系统性红斑狼疮（SLE）这一假设是，SLE患者中， 非洲或美洲印第安人血统基因单独或与环境因素相结合，包括低 个体和组水平的SES结构，具有更严重和快速进展的SLE，如由几个 纵向临床和可溶性生物标志物指数。为了解决这个假设，我们打算（1）使用面板， 建立了祖先信息标记（AIM），以分别估计个体混合的程度， 欧洲裔美国人（EA）、非洲裔美国人（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，有和无肾脏受累和器官损害的SLE患者 （2）确定这些组中个体混合物的估计与 至肾脏受累和器官损伤指数的时间;以及（3）确定个体-和 组水平的SES结构修改了个体混合物对 SLE患者肾脏受累和器官损害的存在/不存在、时间和严重程度。使用 符合11项ACR标准中4项的当前和新入组SLE患者的扩展PROFILE队列， 参与美国大陆、波多黎各和墨西哥的8个研究中心，我们打算利用靶向 独立和共同贡献的遗传祖先，使用良好表征的AIM，和环境（SES） 与SLE进展克里思有关的因素。汇总研究人群将代表最大的多种族 这将允许对SLE患者的基因和环境因素进行全面评估。 影响是由种族/民族的二态性。这种方法提供了最好的机会，快速利用这些 的关系，并提供新的见解SLE的过程和结果。从这个纵向的结果 调查将解决关键问题，以了解环境因素的相对贡献， 可能解释SLE相关发病率、严重程度和进展的不同趋势的遗传祖先 这在非洲人和西班牙人后裔中很常见。 项目与总体PPG优先级的关系。拟议的研究计划旨在研究 遗传祖先标记和环境因素在进展速度和严重程度方面的相互作用 关于SLE该研究计划将（1）最大限度地发挥所有四个PPG项目以及行政管理之间的协同作用， 和遗传流行病学和生物统计学核心，从而促进我们所述的具体的严格评估， （2）加强伙伴机构之间的合作，（3）促进 继续发展有效的风湿病研究计划，（4）加强研究工作 对SLE相关的健康差异和（5）提供新的见解，这种神秘的遗传病因学 自身免疫表型在少数民族人群中不成比例地更频繁和严重。在 这种能力，这项研究可能被用来最终缩小差距在SLE发病率和死亡率， 在非裔美国人和西班牙裔人群中观察到。

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.