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
- 来源:
- 关键词:AddressAffectAfrican ancestryAgeAllelesAntigen-Antibody ComplexAsian ancestryAutoimmune DiseasesB-LymphocytesBiological AssayCRISPR/Cas technologyCaucasiansCell LineCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsDataDepositionDevelopmentDiagnosisDiagnosticDiseaseDizygotic TwinsDrug TargetingEnhancersEpigenetic ProcessEthnic OriginEtiologyFutureGene ExpressionGenesGeneticGenetic Predisposition to DiseaseGenomicsHispanic ancestryImmuneIndividualInterventionKidneyKnowledgeLeadLightLinkLinkage DisequilibriumLupusLupus ErythematosusMeta-AnalysisMethodsMolecularMonozygotic twinsNucleic Acid Regulatory SequencesOrganPathogenesisPathologicPatientsPlant RootsPredispositionPrevalenceProductionProteinsRaji CellRecurrenceRegulatory ElementResearchResolutionRiskRunningSiblingsSingle Nucleotide PolymorphismSingle Nucleotide Polymorphism in Regulatory SequenceSkinSusceptibility GeneSystemic Lupus ErythematosusT cell responseTechniquesTestingTimeTranslationsUntranslated RNAValidationVariantWomanWorkbasecausal variantcell typeclinical applicationcurative treatmentseffective therapyeffectiveness validationfollow-upgene interactiongenome wide association studygenome-widehigh rewardhigh riskinsightmultiorgan damagenext generationnext generation sequencingnovelnovel therapeuticspathogenic autoantibodiespreventpublic health relevanceresponserisk varianttherapeutic target
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
系统性红斑狼疮(SLE或狼疮)是一种目前无法治愈的自身免疫性疾病,其特征在于
异常免疫细胞(例如,B淋巴细胞)反应和多种病原体的产生
自身抗体,最终导致多器官损伤(例如,肾脏、皮肤)。虽然SLE的病因不完全
在理解的基础上,充分确定了实质性的遗传贡献。几项全基因组关联研究
(GWAS)已经确定了超过100个SLE易感基因座(p<5x 10 -8),主要是单核苷酸多态性
(SNP)。这些SNPs中的大多数并不直接改变蛋白质产物,我们和其他人以前的工作已经证明了这一点。
显示许多这样的SNP在顺式调节元件(cRE)内富集(即,增强剂和消音剂)
并可能调节基因表达。然而,精确定位克雷斯内的因果、易感SNP,
破译其确切机制是该领域取得进展的主要障碍。因此,这
知识鸿沟严重阻碍了GWAS研究结果转化为临床应用。因此,
是一个深刻的需要公正的,全面的,和高通量的方法来解决机制,
数百个潜在的调节SNP(rSNP)与SLE易感性之间存在联系。我们假设SLE-
诱发rSNPs异常诱导cRE活性,影响未受刺激的细胞中靶基因的表达。
和/或刺激的B细胞。为了系统地描述rSNPs及其对靶基因的影响,我们建议
建立一个高通量的实验管道,以确定和验证GWAS基因座的rSNP。在
目的一、应用高通量的自转录活性调控区测序技术
(STARR-seq)来功能性地量化数百个含有SNP的区域的调节活性。
同步使用Raji细胞(B淋巴细胞)在未刺激和刺激条件下,我们将应用
STARR-seq评估79个不同GWAS基因座内756个选定rSNP的SLE易感性。在目标2a中,我们
将应用下一代(NG)-Capture-C来检测SNP对顺式与内源性相互作用的特异性影响,
Raji细胞中的同源靶基因,不需要强的靶基因和功能的先验假设,
后果我们将评估Aim 1和Aim 2a中相同的756个SNP。我们预计这种双管齐下的
串联策略将弥合GWAS衍生的rSNP和与其靶基因的机制链接之间的差距。
为了验证所提出的方法的有效性和准确性,Aim 2b将使用基于CRISPR的
(epi)对选定的rSNP进行基因编辑,以验证对内源性靶标的等位基因特异性功能效应
在同基因细胞中的基因。总的来说,提出的无偏的方法,发现和验证系统性红斑狼疮,
“因果”SNP是高风险/高回报的,可能导致对SLE病因学的理解取得突破,
干预策略。rSNPs、克雷斯及其靶基因的发现将大大推进我们的研究。
SLE遗传学的知识,以及未来深入研究SLE的贡献机制的方向。
rSNPs和靶基因在狼疮易感性,这可能会定义未来的治疗目标来自GWAS。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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