High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus
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 (encoded by 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 regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.
Authors
- Brian Wauford
- Vitor R. C. Aguiar (ORCID: https://orcid.org/0000-0002-4137-9518)
- Miranda C. Marion (ORCID: https://orcid.org/0000-0003-4487-8010)
- Jeffrey A. Sparks (ORCID: https://orcid.org/0000-0002-5556-4618)
- Carl D. Langefeld
- S.I. Sim (ORCID: https://orcid.org/0009-0005-4502-0923)
- Taehyeung Kim (ORCID: https://orcid.org/0000-0003-4758-0578)
- María Gutiérrez‐Arcelus (ORCID: https://orcid.org/0000-0001-7898-7691)
- Peter A. Nigrović
- Jing Cui (ORCID: https://orcid.org/0000-0001-8657-1741)
- Marc Todd
- Matthew T. Weirauch (ORCID: https://orcid.org/0000-0001-7977-9122)
- Marta Martínez‐Bonet (ORCID: https://orcid.org/0000-0003-0715-403X)
- Qiang Wang (ORCID: https://orcid.org/0000-0001-5939-8461)
- Xiaoting Chen (ORCID: https://orcid.org/0000-0002-3782-3962)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Cincinnati Children's Hospital Medical Center (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Hospital General Universitario Gregorio Marañón (ES)
- Wake Forest University (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s41467-024-50710-5
- Citations
- 6
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Gilead Sciences
- Lupus Research Alliance
- National Research Foundation
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases