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.
项目总结
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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