The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1.
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.
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Gang
G
Li
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Pierre
P
Cunin
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Department of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.|Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Di
D
Wu
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
Dorothée
D
Diogo
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Yu
Y
Yang
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.
Yukinori
Y
Okada
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Robert M
RM
Plenge
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.|Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
Peter A
0000-0002-2126-3702
PA
Nigrovic
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002460:Cell Line; D045325:HCT116 Cells; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D054399:Receptors, CCR6 / Q000235:genetics* / Q000378:metabolism
C106311:CCR6 protein, human; D054399:Receptors, CCR6; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1