High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus.
Lupus Erythematosus, Systemic
/ genetics
Humans
Polymorphism, Single Nucleotide
Ikaros Transcription Factor
/ genetics
I-kappa B Kinase
/ genetics
Genome-Wide Association Study
Genetic Predisposition to Disease
/ genetics
Alleles
B-Lymphocytes
/ metabolism
NF-kappa B
/ metabolism
Gene Expression Regulation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 Aug 2024
09 Aug 2024
Historique:
received:
14
08
2023
accepted:
17
07
2024
medline:
10
8
2024
pubmed:
10
8
2024
entrez:
9
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39122710
doi: 10.1038/s41467-024-50710-5
pii: 10.1038/s41467-024-50710-5
doi:
Substances chimiques
Ikaros Transcription Factor
148971-36-2
I-kappa B Kinase
EC 2.7.11.10
IKZF1 protein, human
0
IKBKE protein, human
EC 2.7.11.10
NF-kappa B
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6804Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ID : 2R01AR065538
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ID : R01AR075906
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ID : R01AR073201
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ID : P30AR070253
Informations de copyright
© 2024. The Author(s).
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