The goal of Project 4 is to delineate the complex interactions between genetic ancestry andenvironmental factors in the rate of progression and severity of renal involvement and organ damage associatedwith systemic lupus erythematosus (SLE). The hypothesis is that SLE patients with a greater percentage ofAfrican or Amerindian ancestry genes both alone and in combination with environmental factors, including lowindividual- and group-level SES constructs, have more severe and rapidly progressive SLE as defined by severallongitudinal clinical and soluble biomarker indices. To address this hypothesis, we intend to (1) use panels ofestablished ancestry informative markers (AIMs) to estimate the extent of individual admixture separately amongEuropean 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 confoundingfactors; (2) determine the extent to which the estimates of individual admixture among these groups relate to thetime to indices of renal involvement and organ damage; and (3) determine the extent to which individual- andgroup-level SES constructs modify the effect (additive joint effects and epistasis) of individual admixture on thepresence/absence, time to and severity of renal involvement and organ damage among patients with SLE. Usingthe expanded PROFILE cohort of current and newly enrolled SLE patients meeting 4 of 11 ACR criteria from theparticipating 8 study sites in the continental US, Puerto Rico and Mexico, we intend to exploit targetedindependent 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-ethnicpopulation to date of SLE patients, which will allow for a comprehensive evaluation of gene and environmentalinfluences that are dimorphic by race/ethnicity. This approach offers the best opportunity to rapidly exploit theserelationships and to provide novel insight into the course and outcome of SLE. Results from this longitudinalinvestigation will address key questions for understanding the relative contributions of environmental factors andgenetic ancestry that may account for the disparate trends of SLE-related morbidities, severity and progressionthat is observed among populations of African and Hispanic ancestries.Relationship of Project with Overall PPG Priorities. The proposed research plan is designed to examine theinteractions between genetic ancestry markers and environmental factors in the rate of progression and severityof SLE. This research plan will (1) maximize synergy between all four PPG projects as well as the Administrativeand Genetic Epidemiology and Biostatistics Cores thereby facilitating a rigorous evaluation of our stated specificaims in a time and cost-effective manner, (2) increase collaboration between partner institutions, (3) foster thecontinued development of an effective Rheumatic Diseases Research Program, (4) enhance research effortstoward SLE-related health disparities and (5) provide novel insight to the genetic etiology of this enigmaticautoimmune phenotype that is disproportionately more frequent and severe among ethnic minority populations. Inthis capacity, this investigation may be used to ultimately narrow the gap in SLE morbidity and mortality that isdisparately observed between African Americans and Hispanic populations.
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