Connecting the gap between GWAS and functional targets for lupus susceptibility

连接 GWAS 和狼疮易感性功能目标之间的差距

基本信息

  • 批准号:
    10433444
  • 负责人:
  • 金额:
    $ 26.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-05 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Systematic lupus erythematosus (SLE or lupus) is a currently incurable autoimmune disease, characterized by abnormal immune cell (e.g., B-lymphocytes) response and the production of numerous pathogenic autoantibodies, culminating in multi-organ damage (e.g., kidneys, skin). While the etiology of SLE is incompletely understood, a substantial genetic contribution is well established. Several genome-wide association studies (GWAS) have identified over 100 SLE predisposing loci (p<5x10-8), mostly single nucleotide polymorphisms (SNPs). Most of these SNPs do not directly alter protein products, and previous work from us and others have shown that many such SNPs are enriched within cis regulatory elements (cRE) (i.e., enhancers and silencers) and likely to modulate gene expression. However, pinpointing the causal, predisposing SNPs within cREs and deciphering their precise mechanisms represent major obstacles to progress in the field. Consequently, this knowledge gap has severely hindered the translation of GWAS findings into clinical applications. Hence, there is a profound need for unbiased, comprehensive, and high-throughput approaches to address the mechanistic link between hundreds of potential regulatory SNPs (rSNPs) and SLE susceptibility. We hypothesize that SLE- predisposing rSNPs aberrantly induce cRE activities that influence the expression of target genes in unstimulated and/or stimulated B-cells. To systematically delineate rSNPs and their impact on target genes, we propose to establish a high-throughput experimental pipeline to determine and validate rSNPs underlying GWAS loci. In Aim 1, we will apply the high-throughput technique “Self-Transcribing Active Regulatory Region-sequencing” (STARR-seq) to functionally quantify the regulatory activities of hundreds of SNP-containing regions simultaneously. Using Raji cells (B-lymphocyte) in both unstimulated and stimulated conditions, we will apply STARR-seq to evaluate 756 selected rSNPs within 79 distinct GWAS loci for SLE susceptibility. In Aim 2a, we will apply next-generation (NG)-Capture-C to detect SNP-specific effects on cis interactions with endogenous, cognate target genes in Raji cells, needing no strong a priori hypothesis of target genes and functional consequences. We will evaluate the same set of 756 SNPs in Aim 1 and Aim 2a. We anticipate this two-prong tandem strategy will bridge the gap between GWAS-derived rSNPs and mechanistic links to their target genes. To validate the effectiveness and accuracy of the proposed methods, Aim 2b will use CRISPR-based (epi)genetic editing of a selected rSNP to validate the allele-specific functional effects on the endogenous target gene(s) in isogenic cells. Collectively, the proposed unbiased approaches for discovering and validating SLE “causal” SNPs is high risk/high reward and may lead to breakthroughs in the understanding of SLE etiology and intervention strategies. Discovery of rSNPs, cREs, and their target genes will significantly advance our knowledge of SLE genetics, and yield directions for future in-depth mechanistic research on the contribution of rSNPs and target genes in lupus susceptibility, which could define future therapeutic targets derived from GWAS.
摘要

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Swapan K. Nath其他文献

Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.
白癜风的遗传流行病学:多位点隐性交叉验证。
  • DOI:
  • 发表时间:
    1994
  • 期刊:
  • 影响因子:
    9.8
  • 作者:
    Swapan K. Nath;Partha P. Majumder;James J. Nordlund
  • 通讯作者:
    James J. Nordlund
potential for generating B cells with a diverse immunoglobulin repertoire Human fetal, cord blood, and adult lymphocyte progenitors have similar
产生具有多种免疫球蛋白库的 B 细胞的潜力 人类胎儿、脐带血和成人淋巴细胞祖细胞具有相似的特性
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Grant R. Kolar;Takafumi Yokota;Maria Isabel D. Rossi;Swapan K. Nath;J. D. Capra
  • 通讯作者:
    J. D. Capra

Swapan K. Nath的其他文献

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{{ truncateString('Swapan K. Nath', 18)}}的其他基金

Contributions of autophagy-related genes in lupus
自噬相关基因在狼疮中的贡献
  • 批准号:
    10682136
  • 财政年份:
    2023
  • 资助金额:
    $ 26.22万
  • 项目类别:
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
  • 批准号:
    10618360
  • 财政年份:
    2022
  • 资助金额:
    $ 26.22万
  • 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
  • 批准号:
    9895394
  • 财政年份:
    2020
  • 资助金额:
    $ 26.22万
  • 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
  • 批准号:
    10115587
  • 财政年份:
    2020
  • 资助金额:
    $ 26.22万
  • 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
  • 批准号:
    8995183
  • 财政年份:
    2015
  • 资助金额:
    $ 26.22万
  • 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
  • 批准号:
    8823171
  • 财政年份:
    2015
  • 资助金额:
    $ 26.22万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    9259737
  • 财政年份:
    2014
  • 资助金额:
    $ 26.22万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    8776043
  • 财政年份:
    2014
  • 资助金额:
    $ 26.22万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    9053279
  • 财政年份:
    2014
  • 资助金额:
    $ 26.22万
  • 项目类别:
NADPH-Oxidase and SLE Susceptibility
NADPH 氧化酶和 SLE 易感性
  • 批准号:
    8651414
  • 财政年份:
    2013
  • 资助金额:
    $ 26.22万
  • 项目类别:

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