Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by autoantibody production and immune complex formation. Genetic predisposition to SLE has been well characterized with over two decades of work in human and murine models, however the precise genetic variants responsible have, with few exceptions, remained elusive. With the advent of high-density single nucleotide polymorphism (SNP) maps based on the complete sequence of the human genome and the ability to genotype these polymorphisms using high density arrays in thousand of subjects, the genetic landscape of SLE is being revealed with unprecedented resolution. Recently published work from our laboratory has identified and confirmed a convincing novel association with TNFAIP3 (A20), a critical negative regulator of NF-kB signaling. New preliminary data presented in this amended proposal demonstrates that the TNFAIP3 association is convincingly replicated in multiple independent European-derived SLE sample collections with a meta-analysis P-value of 1.51x10-15 (OR=2.09) for the best marker, rs5029939. Through imputation, we identify 11 new associated variants and define the limits of the TNFAIP3 SLE risk haplotype to a 109 kb DNA segment that spans the TNFAIP3 coding region. Using a coordinated bioinformatics approach, we evaluated the functional potential for each SNP on the risk haplotype and determined that it is unlikely that any of the currently typed or imputed SNPs are responsible for the genetic association. Finally, preliminary functional data suggest that the SLE risk alleles in the TNFAIP3 locus result in a defect in TNFAIP3 expression and regulation of NF-kB activation. The primary objectives of this project are focused on isolating the precise variant responsible for the association in the region of TNFAIP3 in human SLE. We will do this by testing the hypothesis that the association extends to SLE cohorts of non-European ancestry. We will exploit differences in population haplotype structure to narrow the SLE risk interval using a trans-racial mapping approach. In parallel, we will deeply resequence the region, focusing first on promoter, exons and UTR regions using conventional sequencing. We will, however, rapidly employ sequence capture and massively parallel sequencing technology to resequence the entire risk haplotype when fully operational. Finally, we will test the """"""""expression phenotype"""""""" hypothesis and the """"""""F127C"""""""" hypothesis as likely functional effects of the SLE associated risk haplotype. When complete, we expect to have identified the precise variant(s) responsible for association with SLE in European American, African American, Asian and Hispanic populations. We expect to have an initial mechanistic understanding for how the associated variants alter A20 structure and function in a manner that predisposes to autoimmunity. These results should add significantly to our understanding of the genetic and pathophysiologic basis of SLE and lead to improvements for patients with SLE and related autoimmune disorders for which variants in TNFAIP3 portend risk.
Systemic lupus erythematosus is a severe, debilitating autoimmune disease that represents a significant healthcare burden worldwide. Our study will characterize a genetic association between SLE and TNFAIP3, a gene critical for controlling inflammation and immune system function. This work has the potential to lead to new treatments for SLE and to new tests for diagnosing and monitoring the disease.
|Pelikan, Richard C; Kelly, Jennifer A; Fu, Yao et al. (2018) Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat Commun 9:2905|
|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 :|
|Fu, Yao; Tessneer, Kandice L; Li, Chuang et al. (2018) From association to mechanism in complex disease genetics: the role of the 3D genome. Arthritis Res Ther 20:216|
|Wang, Chih-Chuan; Ortiz-González, Xilma R; Yum, Sabrina W et al. (2018) ?IV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy. Am J Hum Genet 102:1158-1168|
|Zhao, Jian; Ma, Jianyang; Deng, Yun et al. (2017) A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet 49:433-437|
|Demirci, F Yesim; Wang, Xingbin; Kelly, Jennifer A et al. (2016) Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry. Arthritis Rheumatol 68:174-83|
|Wang, S; Wen, F; Tessneer, K L et al. (2016) TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus. Genes Immun 17:165-70|
|Ward, Julie M; Ratliff, Michelle L; Dozmorov, Mikhail G et al. (2016) Human effector B lymphocytes express ARID3a and secrete interferon alpha. J Autoimmun 75:130-140|
|Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-1300|
|Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9|
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