High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus

Year: 2024

Type: article

Abstract: Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (IKZF1), thereby modulating expression of IKBKE . Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKε. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a new regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.

Source: Nature Communications

DOI: 10.1038/s41467-024-50710-5

Authors: Qiang Wang, Taehyeung Kim, Marta Martínez-Bonet, Vitor R. C. Aguiar, Sangwan Sim, Jing Cui, Jeffrey A. Sparks, Xiaoting Chen, Marc Todd, Brian Wauford, Miranda C. Marion, Carl D. Langefeld, Matthew T. Weirauch, Maria Gutierrez-Arcelus, Peter A. Nigrovic

Institutions: Boston Children's Hospital, Harvard University, Brigham and Women's Hospital, Instituto de Investigación Sanitaria Gregorio Marañón, Broad Institute, Cincinnati Children's Hospital Medical Center, Wake Forest University Health Sciences, Wake Forest University, University of Cincinnati

Language: English

Topic: Systemic Lupus Erythematosus Research

Subfield: Rheumatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $6,790

Funders: U.S. Department of Health and Human Services, Arthritis National Research Foundation, Gilead Sciences, Lupus Research Alliance, National Research Foundation, National Institutes of Health, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases

OpenAlex ID: W4401461721