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.
抽象的
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,其特征是
免疫细胞(例如 B 淋巴细胞)反应异常以及大量致病菌的产生
自身抗体,最终导致多器官损伤(例如肾脏、皮肤)。虽然 SLE 的病因尚不完全
众所周知,遗传因素的显着贡献已得到证实。多项全基因组关联研究
(GWAS) 已鉴定出超过 100 个 SLE 易感位点 (p<5x10-8),大部分是单核苷酸多态性
(SNP)。大多数这些 SNP 不会直接改变蛋白质产物,我们和其他人之前的工作已经证明
研究表明,许多此类 SNP 在顺式调控元件 (cRE)(即增强子和沉默子)中富集
并可能调节基因表达。然而,查明 cRE 中的因果性、易感性 SNP 和
破译其精确机制是该领域取得进展的主要障碍。因此,这
知识差距严重阻碍了 GWAS 研究结果转化为临床应用。因此,有
迫切需要公正、全面和高通量的方法来解决机械问题
数百个潜在的监管 SNP (rSNP) 与 SLE 易感性之间的联系。我们假设 SLE-
易感 rSNP 异常诱导 cRE 活性,从而影响未受刺激的靶基因的表达
和/或刺激的 B 细胞。为了系统地描述 rSNP 及其对靶基因的影响,我们建议
建立高通量实验流程来确定和验证 GWAS 位点的 rSNP。在
目标1,我们将应用高通量技术“自转录活性调节区测序”
(STARR-seq) 对数百个含有 SNP 的区域的调控活动进行功能量化
同时地。在未刺激和刺激条件下使用 Raji 细胞(B 淋巴细胞),我们将应用
STARR-seq 评估 79 个不同 GWAS 位点内的 756 个选定的 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 对与内源性顺式相互作用的特异性影响,
Raji 细胞中的同源靶基因,不需要靶基因和功能的强先验假设
结果。我们将评估目标 1 和目标 2a 中的同一组 756 个 SNP。我们预计这将分为两方面
串联策略将弥合 GWAS 衍生的 rSNP 与其目标基因的机械联系之间的差距。
为了验证所提出方法的有效性和准确性,Aim 2b 将使用基于 CRISPR 的
对选定的 rSNP 进行(表观)遗传编辑,以验证对内源靶标的等位基因特异性功能效应
同基因细胞中的基因。总的来说,提出的用于发现和验证 SLE 的公正方法
“因果”SNP 具有高风险/高回报,可能会导致对 SLE 病因学和认识的突破。
干预策略。 rSNP、cRE 及其靶基因的发现将显着推进我们的研究
SLE 遗传学知识,并为未来深入机制研究的贡献提供方向
rSNP 和狼疮易感性中的靶基因,可以定义来自 GWAS 的未来治疗靶点。
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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