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

Author

Listed:
  • Qiang Wang

    (Harvard Medical School)

  • Taehyeung Kim

    (Harvard Medical School)

  • Marta Martínez-Bonet

    (Harvard Medical School
    Instituto de Investigación Sanitaria Gregorio Marañón)

  • Vitor R. C. Aguiar

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • 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
    Wake Forest University School of Medicine)

  • Carl D. Langefeld

    (Wake Forest University School of Medicine
    Wake Forest University School of Medicine)

  • Matthew T. Weirauch

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Cincinnati)

  • Maria Gutierrez-Arcelus

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Peter A. Nigrovic

    (Harvard Medical School
    Harvard Medical School)

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.

Suggested Citation

  • 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 , 2024. "High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50710-5
    DOI: 10.1038/s41467-024-50710-5
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    References listed on IDEAS

    as
    1. Yong-Fei Wang & Yan Zhang & Zhiming Lin & Huoru Zhang & Ting-You Wang & Yujie Cao & David L. Morris & Yujun Sheng & Xianyong Yin & Shi-Long Zhong & Xiaoqiong Gu & Yao Lei & Jing He & Qi Wu & Jiangshan, 2021. "Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Deborah S Cunninghame Graham & David L Morris & Tushar R Bhangale & Lindsey A Criswell & Ann-Christine Syvänen & Lars Rönnblom & Timothy W Behrens & Robert R Graham & Timothy J Vyse, 2011. "Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus," PLOS Genetics, Public Library of Science, vol. 7(10), pages 1-9, October.
    3. Xiaoming Lu & Xiaoting Chen & Carmy Forney & Omer Donmez & Daniel Miller & Sreeja Parameswaran & Ted Hong & Yongbo Huang & Mario Pujato & Tareian Cazares & Emily R. Miraldi & John P. Ray & Carl G. Boe, 2021. "Global discovery of lupus genetic risk variant allelic enhancer activity," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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