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 ar...

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Bibliographic Details
Published in:PLoS genetics 2016-09, Vol.12 (9), p.e1006292-e1006292
Main Authors: Li, Gang, Cunin, Pierre, Wu, Di, Diogo, Dorothée, Yang, Yu, Okada, Yukinori, Plenge, Robert M, Nigrovic, Peter A
Format: Article
Language:English
Subjects:
Arthritis, Rheumatoid - genetics
Biology and life sciences
Cell Line
Colleges & universities
Deoxyribonucleic acid
DNA
Engineering and technology
Funding
Gene expression
Genetic aspects
Genetic engineering
Genetic variation
Genomes
HCT116 Cells
Health aspects
Hospitals
Humans
Immunology
Laboratories
Medical research
Medicine and Health Sciences
Pathogenesis
Poly (ADP-Ribose) Polymerase-1 - genetics
Poly (ADP-Ribose) Polymerase-1 - metabolism
Polymorphism, Genetic
Proteins
Receptors, CCR6 - genetics
Receptors, CCR6 - metabolism
Research and Analysis Methods
Rheumatoid arthritis
Rheumatology
Statistical analysis
Womens health
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006292