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The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1
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نویسنده
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li g. ,cunin p. ,wu d. ,diogo d. ,yang y. ,okada y. ,plenge r.m. ,nigrovic p.a.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 9
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چکیده
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Understanding the implications of genome-wide association studies (gwas) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. the non-coding triallelic dinucleotide polymorphism ccr6dnp is associated with risk for rheumatoid arthritis,and is considered likely causal because allelic variation correlates with expression of the chemokine receptor ccr6. using transcription activator-like effector nuclease (talen) gene editing,we confirmed that ccr6dnp regulates ccr6. to identify the associated transcription factor,we applied a novel assay,flanking restriction enhanced pulldown (frep),to identify specific association of poly (adp-ribose) polymerase 1 (parp-1) with ccr6dnp consistent with the established allelic risk hierarchy. correspondingly,manipulation of parp-1 expression or activity impaired ccr6 expression in several lineages. these findings show that ccr6dnp is a causal variant through which parp-1 regulates ccr6,and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease. © 2016 li et al.
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آدرس
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division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma, United States, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma, United States, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma,united states,department of statistics,harvard university,cambridge,ma,united states,centre for cancer research,monash institute of medical research,monash university,clayton,vic,australia,department of periodontology,university of north carolina at chapel hill,chapel hill,nc, United States, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute,cambridge,ma,united states,merck research laboratories,boston,ma, United States, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma, United States, department of human genetics and disease diversity,graduate school of medical and dental sciences,tokyo medical and dental university,tokyo,japan,laboratory for statistical analysis,riken center for integrative medical sciences,yokohama,japan,department of statistical genetics,osaka university graduate school of medicine,osaka, Japan, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma,united states,merck research laboratories,boston,ma, United States, division of rheumatology,immunology and allergy,brigham and women’s hospital,boston,ma,united states,division of immunology,boston children’s hospital,boston,ma, United States
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Authors
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