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

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 and Peter A. Nigrovic ()
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Qiang Wang: Harvard Medical School
Taehyeung Kim: Harvard Medical School
Marta Martínez-Bonet: Harvard Medical School
Vitor R. C. Aguiar: Harvard Medical School
Sangwan Sim: Harvard Medical School
Jing Cui: Harvard Medical School
Jeffrey A. Sparks: Harvard Medical School
Xiaoting Chen: Cincinnati Children’s Hospital Medical Center
Marc Todd: Harvard Medical School
Brian Wauford: Harvard Medical School
Miranda C. Marion: Wake Forest University School of Medicine
Carl D. Langefeld: Wake Forest University School of Medicine
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Maria Gutierrez-Arcelus: Harvard Medical School
Peter A. Nigrovic: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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 (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.

Date: 2024
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DOI: 10.1038/s41467-024-50710-5

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