The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1

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  • Li, Gang
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Cunin, Pierre
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Wu, Di
    • Affiliation: School of Dentistry, Department of Periodontology
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Diogo, Dorothée
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Yang, Yu
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Okada, Yukinori
    • Other Affiliation: Department of Statistical Genetics; Osaka University Graduate School of Medicine
  • Plenge, Robert M.
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
  • Nigrovic, Peter A.
    • Other Affiliation: Division of Rheumatology; Immunology and Allergy; Brigham and Women’s Hospital
Abstract
  • 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.
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  • Article
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  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 12
Journal issue
  • 9
Page start
  • e1006292
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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