High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus.
Qiang WangTaehyeung KimMarta Martínez-BonetSangwan SimVitor AguiarJing CuiJeffrey A SparksXiaoting ChenMarc ToddBrian WaufordMatthew T WeirauchMaria Gutierrez-ArcelusPeter A NigrovicPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- systemic lupus erythematosus
- transcription factor
- genome wide
- genome wide association
- disease activity
- high throughput
- rheumatoid arthritis
- signaling pathway
- copy number
- endothelial cells
- oxidative stress
- dna methylation
- single cell
- acute lymphoblastic leukemia
- dna binding
- lps induced
- nuclear factor
- rna seq
- drug induced