Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by the presence of antinuclear autoantibodies, complement activation and multisystem organ damage. Trends in SLE prevalence and clinical course differ by ancestry. The basis for this disparity remains poorly understood. Although the etiology of SLE is unclear, combinations of genetic and environmental factors play a causal role. The goal of the proposed investigation is to delineate the independent and combined effects of variation in DNA sequence with novel high resolution autoantibody profiles relative to the rate of progression and severity of lupus nephritis (LN) and severe organ damage among patients with SLE. We will test the overarching hypothesis that the genetic effect on extreme-trait SLE endophenotypes resulting from variation in multiple loci is stronger among persons with specific autoantibody profiles, which may account for the disparity observed among patients of African and Amerindian ancestry. To test this overarching hypothesis, we intend to determine the: (1) contribution of autoantibody specificity on the presence of and time to extreme-trait SLE endophenotypes, and differences by ancestry, using novel high resolution antigen microarrays, (2) contribution of variation in DNA sequence on the presence of and time to extreme-trait SLE endophenotypes using Illumina high throughput technologies and (3) extent to which variation in DNA sequence modifies the effect of autoantibody specificity on the presence, and time to, extreme- trait SLE endophenotypes. The proposed research is an innovative, timely and comprehensive strategy to identify novel genetic and serial autoantibody signature contributions to SLE clinical course. We will capitalize on a unique opportunity to explore cross-sectional and longitudinal outcomes with variation in DNA sequence and autoantibodies obtained from ethnically diverse, well-characterized population of SLE patients while taking advantage of recent technological advances in human genome sequencing and high resolution antigen microarray technologies. Within the scope of this proposal, we intend to leverage existing collaborations, resources and comprehensive, high quality, clinical data and genotyping collected in a well-characterized SLE inception cohort, to fill a critical gap in knowledge required to develop efforts to detect, prevent, manage and treat SLE. This approach offers the best opportunity to comprehensively characterize novel genetic and autoantibody relationships with SLE clinical course as a prognostic index for targeting high-risk vulnerable populations that may benefit from individualized clinical management or therapeutic intervention.
Systemic lupus erythematosus results, in part, from genetic abnormalities such as mutations that lead to an altered immune response. The purpose of this study is to characterize complex interactions between variation in DNA sequence and autoantibody profiles with the rate of progression and severity of lupus-associated nephritis and severe organ damage, which are more common among ethnic minorities. The knowledge gained from this study may help us to lower the risk of lupus-related clinical manifestations and to manage and treat it more effectively.
|Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :|
|Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013|
|Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52|
|Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50|
|Arroyo-Ávila, Mariangelí; Santiago-Casas, Yesenia; McGwin Jr, Gerald et al. (2015) Clinical associations of anti-Smith antibodies in PROFILE: a multi-ethnic lupus cohort. Clin Rheumatol 34:1217-23|
|Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62|
|Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98|