Mechanistic Characterization of GWAS Loci in SLE

Oklahoma Medical Research Foundation, Oklahoma City OK

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Abstract

? DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a debilitating autoimmune disease with substantial heritability. It is characterized by a broad spectrum of clinical manifestations including pathogenic autoantibody production and multi-system organ damage. Compared to European-Americans (EA), Asians have at least 3-fold higher prevalence of SLE and more severe clinical manifestations, including life-threatening kidney damage. Genetic variation between ethnicities could account for underlying differences in disease severity and clinical manifestations. Development of new and more effective approaches for prevention and treatment requires improved understanding of disease mechanisms. While recent genome-wide association studies (GWAS) have identified over 40 genes/loci, differentiating between pathological and benign DNA changes is a major challenge. Lack of understanding causal effects underlying GWAS signals has hindered development of SLE diagnostics and treatments. GWAS results indicate that the genetic architecture of SLE in Asians may differ from more extensively studied European-derived populations. Thus, it is necessary to identify primary causal variants that influence SLE development in Asian populations. Our research team has the experience, expertise, resources and infrastructure necessary to move beyond GWAS to accelerate the discovery of causal variants underlying these signals and their functional effects. We have successfully identified SLE predisposing variants from IFIH1, ITGAM, and NCF2 loci, and experimentally defined mechanisms influencing SLE risk. Based on our preliminary data from >11,000 Koreans and Chinese, we propose to study 6 highly significant (10-99<P<10-11) candidate gene/loci in Asians. Four of these loci are novel, not reported in earlier GWAS. Our long-term goals are to detect functional variants from these genes, associate them with SLE symptoms, and define their biological mechanisms. Aim 1 is to pinpoint functional variants within 6 candidate genes in Asian populations by performing deep sequencing followed by imputation-based association analysis. We will also define the relationship between these variants and SLE clinical sub-phenotypes and autoantibody profiles. Significant SNPs, especially rare variants, will be validated with follow-up genotyping. Aim 2 is to predict and validate mechanistic effects of SLE-predisposing variants. We will employ bioinformatic analysis and molecular modeling to prioritize associated variants and select putative SNPs for appropriate experimental validation by adapting our established pipeline for functional assays. We will also identify networks involving our target predisposing SNPs, and genes affecting pathways that could influence SLE pathogenesis. Finally, we will experimentally validate functional effects of variants to define disease mechanisms. These results will provide new insights into mechanisms by which these variants contribute to lupus, and accelerate identification and validation of novel targets as well as development of treatments and future therapeutic interventions for lupus.