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Cited by 279Systemic Lupus Erythematosus ResearchGenetic Associations and EpidemiologyGenomics and Chromatin Dynamics

Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

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Adrianto, Indra, Wen, Feng, Templeton, Amanda, Wiley, Graham, King, Jarrod B, Lessard, Christopher J, Bates, Jared S, Hu, Yanqing +39 more·2011·Nature Genetics
DOI 10.1038/ng.766PMC PMC3103780
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Abstract

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

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  • A systemic lupus erythematosus-associated variant (TT > A) situated within an enhancer downstream of TNFAIP3 abrogates NF-kB binding, affecting TNFAIP3 expression.

    “In another example, a systemic lupus erythematosus-associated variant (termed TT > A) situated within an enhancer downstream of TNFAIP3 has been shown to abrogate NF-kB binding, affecting TNFAIP3 expression [211, 212].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [211]

    The Abstract identifies the SLE-associated TT>A variant downstream of TNFAIP3 and reports reduced binding by a complex containing NF-κB subunits, along with reduced TNFAIP3 expression on the variant-carrying haplotype. It does not show that NF-κB binding was abrogated: the binding-assay passage reports a difference in binding intensity, while the discussion says the precise mechanism linking the variant to expression remains uncertain. (LLM, conf=0.88)

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References 36 · Cited by 279

Research works printed but not linked: 27

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Authors
Adrianto, I., Wen, F., Templeton, A., Wiley, G., King, J. B., Lessard, C. J., Bates, J. S., Hu, Y., Kelly, J. A., Kaufman, K. M., Guthridge, J. M., Alarcón-Riquelme, M. E., Anaya, J.-M., Bae, S.-C., Bang, S.-Y., Boackle, S. A., Brown, E. E., Petri, M. A., Gallant, C., Ramsey-Goldman, R., Reveille, J. D., Vila, L. M., Criswell, L. A., Edberg, J. C., Freedman, B. I., Gregersen, P. K., Gilkeson, G. S., Jacob, C. O., James, J. A., Kamen, D. L., Kimberly, R. P., Martin, J., Merrill, J. T., Niewold, T. B., Park, S.-Y., Pons-Estel, B. A., Scofield, R. H., Stevens, A. M., Tsao, B. P., Vyse, T. J., Langefeld, C. D., Harley, J. B., Moser, K. L., Webb, C. F., Humphrey, M. B., Montgomery, C. G., & Gaffney, P. M.
Affiliations
  • Oklahoma Medical Research Foundation (US)
  • University of Oklahoma Health Sciences Center (US)
  • United States Department of Veterans Affairs (US)
  • Universidad del Rosario (CO)
  • Hanyang University Seoul Hospital (KR)
  • University of Colorado Denver (US)
  • University of Alabama at Birmingham (US)
  • Johns Hopkins University (US)
  • Uppsala University (SE)
  • The University of Texas Health Science Center at Houston (US)
  • University of California, San Francisco (US)
  • Wake Forest University Health Sciences (US)
  • Feinstein Institute for Medical Research (US)
  • Medical University of South Carolina (US)
  • University of Southern California (US)
  • Consejo Superior de Investigaciones Científicas (ES)
  • University of Chicago (US)
  • University of Washington (US)
  • University of California, Los Angeles (US)
  • King's College London (GB)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Gaffney, Patrick M
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-02-20
Volume
43
Issue
3
Pages
253-258
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.766
PMC
PMC3103780
OpenAlex
W2037368171
Cited by
279
References
36
Citations by year
2026: 5 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 19 · 2020: 20 · 2019: 15 · 2018: 18 · 2017: 18 · 2016: 18 · 2015: 25 · 2014: 26 · 2013: 27 · 2012: 32
FWCI
23.39
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Wellcome Trust
  • Versus Arthritis
  • National Institutes of Health (n01ar62277-9-0-1, UL1TR000154, n01ai50026-8-0-1, 5m01rr000079-42)
  • U.S. Public Health Service (R37 24717)
  • National Cancer Institute (R01CA141700)
  • National Institute of General Medical Sciences (P30GM103510)
  • National Institute of Allergy and Infectious Diseases (P01AI083194, L30 AI071651, R01AI063274, R37AI024717, K08AI083790, K24AI078004, N01 AI050026, AI071651, R01AI070983, R21AI070304)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR042460, RC1AR058621, R01AR043274, R01 AR 43814, R01AR033062, P01AR49084, R01 AR 33062, P60AR053308, R01AR051545, N01 AR62277, R01AR043727, P30AR053483, N01-AR062277, P01AR049084, P30 AR055385, P30AR048311, R01AR056360, R01AR043814)
  • National Institute of Dental and Craniofacial Research (R01DE018209)
  • National Center for Research Resources (UL1RR025005, ULI RR025014-02, P20RR020143, M01-RR000079, UL1RR025014, UL1RR024999, M01 RR-00079, P30RR031152, UL1RR025741, P20RR015577)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
systemic lupus erythematosus, A20, genetic susceptibility, fine mapping, functional polymorphisms, NF-kappaB binding, risk haplotype, autoimmune disease genetics, ethnic diversity
MeSH terms
Tumor Necrosis Factor alpha-Induced Protein 3, Base Sequence, DNA-Binding Proteins, Female, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Molecular Sequence Data, Nuclear Proteins, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Intracellular Signaling Peptides and Proteins

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