Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
基本信息
- 批准号:10064581
- 负责人:
- 金额:$ 39.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAllelesArthritisBindingBinding ProteinsBioinformaticsBiologicalBiologyChildChildhoodChronic Childhood ArthritisClustered Regularly Interspaced Short Palindromic RepeatsCodeCollaborationsDNADNA-Protein InteractionDataDiseaseDissectionExperimental GeneticsFamilyFrequenciesGene ExpressionGenesGenetic PolymorphismGenomicsGoalsHaplotypesHumanHuman GeneticsIncubatedIndividualInflammatoryInflammatory ArthritisInfrastructureJointsLibrariesLinkLinkage DisequilibriumLuciferasesMass Spectrum AnalysisMediatingMethodsMolecular TargetNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNuclear ExtractOligonucleotidesPathogenesisPathway interactionsPhenotypePositioning AttributeProbabilityProteinsResearchResearch PersonnelRheumatoid ArthritisRheumatologyRiskRoleSTAT4 geneSamplingSingle Nucleotide PolymorphismSystemTNF receptor-associated factor 1TYK2TechniquesTestingTherapeuticTherapeutic InterventionTranslatingTranslational ResearchTwin Multiple BirthUntranslated RNAValidationVariantWorkarthropathiesbiobankdisorder riskfrontiergenetic associationgenetic regulatory proteingenetic variantgenome wide association studygenome-widegenome-wide analysisgenomic locusinnovationinsightnew therapeutic targetnext generation sequencingnovelranpirnaserisk variantsystemic juvenile idiopathic arthritistherapeutic targettooltranscription factorvalidation studies
项目摘要
Project Summary
Juvenile idiopathic arthritis (JIA) is a diverse family of inflammatory arthritides that begin in childhood.
Genome-wide association studies in the most common phenotype, seronegative oligoarticular plus
polyarticular JIA (sometimes for simplicity termed “polygoJIA”), have identified 27 non-HLA loci associated
with disease risk. GWAS of the most destructive variant, systemic JIA, has defined additional loci. Each of
these “hits” marks a biological pathway in the pathogenesis of JIA.
Unfortunately, pinpointing these mechanisms from GWAS data has proven difficult. GWAS hits mark large
segments of DNA, termed haplotypes. Most of these haplotypes contain no SNPs (single nucleotide
polymorphisms) or other variants that affect coding, suggesting that most causative polymorphisms are
regulatory. Finding regulatory SNPs and the proteins that bind them has proven to be exceptionally difficult,
and as a result GWAS have so far provided limited insight into JIA biology.
To address this roadblock, our lab has recently developed two novel experimental methods. SNP-seq
interrogates candidate regulatory variants using enzymatic restriction followed by next-generation
sequencing to identify those that bind transcription factors and other regulatory proteins. Flanking
Restriction Enhanced Pulldown (FREP) is an efficient method to pull down the associated protein(s) for
identification by mass spectrometry, thereby linking disease-associated variants to particular cellular
pathways. This tandem strategy allows us to bridge the gap between GWAS and mechanism.
The hypothesis underlying this proposal is that experimental dissection of genetic associations will identify
new mechanisms and thus new potential therapeutic targets in JIA. In Aim I, we will pursue SNP-seq +
FREP to identify novel DNA-protein associations that drive polygoJIA risk. We screened 1,223 genetic
polymorphisms in close linkage disequilibrium with 27 polygoJIA risk loci and identified multiple strong
candidate functional variants, including several validated experimentally using techniques including
electrophoretic mobility shift, luciferase and CRISPR. We will confirm these high-probability variants and
then extend the work to other SNP-seq hits. In Aim II, beginning with an independent SNP-seq screen of the
TRAF1/C5 locus, we will employ FREP and other upstream and downstream validation approaches to
define how this locus drives risk of polygoJIA. We will employ SNP-seq + FREP to interrogate recently-
available GWAS findings in systemic JIA to define mechanisms in this unique, highly-inflammatory disease.
Together, these studies will allow us to identify DNA-protein associations that drive the pathogenesis of JIA.
项目摘要
幼年特发性关节炎(JIA)是一个从童年开始的炎症性关节炎的多样化家族。
最常见表型--血清阴性少关节增多症的全基因组相关性研究
多关节JIA(为了简单起见,有时称为“PolygoJIA”),已经确定了27个与非人类白细胞抗原相关的基因座
有疾病风险。最具破坏性的变异--系统性JIA的GWA型已经定义了额外的基因座。每一个
这些“HITS”标志着JIA发病机制中的一条生物学途径。
不幸的是,事实证明,从GWAS数据中准确地确定这些机制是困难的。GWAS的点击率很高
DNA片段,称为单倍型。这些单倍型中的大多数不包含SNPs(单核苷酸
多态)或影响编码的其他变体,这表明大多数导致多态的
监管。事实证明,寻找调节性SNPs和结合它们的蛋白质异常困难,
因此,到目前为止,GWAS对JIA生物学提供的洞察力有限。
为了解决这个障碍,我们的实验室最近开发了两种新的实验方法。SNP-seq
使用酶限制性内切酶询问候选调控变体,然后是下一代
对那些结合转录因子和其他调节蛋白的基因进行测序。侧翼
限制性内切酶增强下拉(FREP)是一种有效的下调相关蛋白(S)的方法
通过质谱学进行鉴定,从而将疾病相关变体与特定细胞联系起来
小路。这一串联战略使我们能够弥合全球气候变化框架和机制之间的差距。
这一提议背后的假设是,对遗传关联的实验性解剖将确定
JIA的新机制和新的潜在治疗靶点。在目标一中,我们将追求SNP-seq+
FREP以确定驱动PolygoJIA风险的新的DNA-蛋白质关联。我们筛选了1,223个基因
27个PolygoJIA风险基因座紧密连锁不平衡的多态现象及多个强连锁
候选功能变体,包括几个经过实验验证的技术,包括
电泳迁移率改变、荧光素酶和CRISPR。我们将确认这些高概率的变种和
然后将这项工作扩展到其他SNP-seq命中。在AIM II中,从独立的SNP-seq屏幕开始
TRAF1/C5基因座,我们将使用FREP和其他上下游验证方法来
定义该基因座如何驱动PolygoJIA的风险。我们将使用SNP-SEQ+FREP来审问最近-
在系统性JIA中可获得的GWAS发现,以确定这种独特的、高度炎症性疾病的机制。
总之,这些研究将使我们能够确定驱动JIA发病机制的DNA-蛋白质关联。
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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Peter A Nigrovic其他文献
Development of consensus best treatment plans for new-onset systemic juvenile idiopathic arthritis
- DOI:
10.1186/1546-0096-10-s1-a50 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Esi M Morgan DeWitt;Timothy Beukelman;Peter A Nigrovic;Karen Onel;Sampath Prahalad;Rayfel Schneider;Matthew Stoll;Carol A Wallace;Yukiko Kimura - 通讯作者:
Yukiko Kimura
Disease characteristics and medication use in a multicenter cohort of children with juvenile idiopathic arthritis (JIA): preliminary analyses from the CARRAnet registry
- DOI:
10.1186/1546-0096-10-s1-a46 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Sarah Ringold;Timothy Beukelman;Esi M Morgan DeWitt;Marc Natter;Peter A Nigrovic;Yukiko Kimura - 通讯作者:
Yukiko Kimura
Juvenile idiopathic arthritis is associated with potentially pathogenic glycosylation of IgG
- DOI:
10.1186/1546-0096-10-s1-a5 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Altan Ercan;Melissa Hazen;Mary Beth Son;Susan Kim;Fatma Dedeoglu;Robert P Sundel;Robert C Fuhlbrigge;Jing Cui;Nancy A Shadick;Michael E Weinblatt;Michael Spigarelli;David N Glass;Susan D Thompson;Peter A Nigrovic - 通讯作者:
Peter A Nigrovic
Peter A Nigrovic的其他文献
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{{ truncateString('Peter A Nigrovic', 18)}}的其他基金
Modulation of neutrophil function through emperipolesis
通过伸入调节中性粒细胞功能
- 批准号:
10091401 - 财政年份:2020
- 资助金额:
$ 39.38万 - 项目类别:
Modulation of neutrophil function through emperipolesis
通过伸入调节中性粒细胞功能
- 批准号:
10656013 - 财政年份:2020
- 资助金额:
$ 39.38万 - 项目类别:
Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
- 批准号:
10675585 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Bridging the gap between GWAS and mechanism in JIA
弥合 GWAS 和 JIA 机制之间的差距
- 批准号:
10622118 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
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