Year: 2016
Type: article
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.
Source: PLoS Genetics
Authors: Gang Li, Pierre Cunin, Di Wu, Dorothée Diogo, Yu Yang, Yukinori Okada, Robert M. Plenge, Peter A. Nigrovic
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: Ly6 family members in neutrophil biology, GWAS to drugs: small molecule screen for inhibitors of CD40 signaling pathway, G6308906652, Development of the novel drug repositioning method based on disease genetics, Identification of biomarkers of autoimmune diseases using HLA imputation, Joint Biology Consortium Resource-based Center
OpenAlex ID: W2520201055