High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus
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 ofIKBKE. 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..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 16. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Qiang [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.08.16.553538 |
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| PPN (Katalog-ID): |
XBI040548813 |
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| 520 | |a 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 ofIKBKE. 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. | ||
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| 700 | 1 | |a Martínez-Bonet, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Aguiar, Vitor R. C. |e verfasserin |4 aut | |
| 700 | 1 | |a Sim, Sangwan |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Sparks, Jeffrey A. |e verfasserin |0 (orcid)0000-0002-5556-4618 |4 aut | |
| 700 | 1 | |a Chen, Xiaoting |e verfasserin |4 aut | |
| 700 | 1 | |a Todd, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Wauford, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Marion, Miranda C. |e verfasserin |4 aut | |
| 700 | 1 | |a Langefeld, Carl D. |e verfasserin |4 aut | |
| 700 | 1 | |a Weirauch, Matthew T. |e verfasserin |0 (orcid)0000-0001-7977-9122 |4 aut | |
| 700 | 1 | |a Gutierrez-Arcelus, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Nigrovic, Peter A. |e verfasserin |0 (orcid)0000-0002-2126-3702 |4 aut | |
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