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Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus
BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677828/ https://www.ncbi.nlm.nih.gov/pubmed/33213505 http://dx.doi.org/10.1186/s13059-020-02184-z |
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author | Raj, Prithvi Song, Ran Zhu, Honglin Riediger, Linley Jun, Dong-Jae Liang, Chaoying Arana, Carlos Zhang, Bo Gao, Yajing Wakeland, Benjamin E. Dozmorov, Igor Zhou, Jinchun Kelly, Jennifer A. Lauwerys, Bernard R. Guthridge, Joel M. Olsen, Nancy J. Nath, Swapan K. Pasare, Chandrashekhar van Oers, Nicolai Gilkeson, Gary Tsao, Betty P. Gaffney, Patrick M. Gregersen, Peter K. James, Judith A. Zuo, Xiaoxia Karp, David R. Li, Quan-Zhen Wakeland, Edward K. |
author_facet | Raj, Prithvi Song, Ran Zhu, Honglin Riediger, Linley Jun, Dong-Jae Liang, Chaoying Arana, Carlos Zhang, Bo Gao, Yajing Wakeland, Benjamin E. Dozmorov, Igor Zhou, Jinchun Kelly, Jennifer A. Lauwerys, Bernard R. Guthridge, Joel M. Olsen, Nancy J. Nath, Swapan K. Pasare, Chandrashekhar van Oers, Nicolai Gilkeson, Gary Tsao, Betty P. Gaffney, Patrick M. Gregersen, Peter K. James, Judith A. Zuo, Xiaoxia Karp, David R. Li, Quan-Zhen Wakeland, Edward K. |
author_sort | Raj, Prithvi |
collection | PubMed |
description | BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis. |
format | Online Article Text |
id | pubmed-7677828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-76778282020-11-20 Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus Raj, Prithvi Song, Ran Zhu, Honglin Riediger, Linley Jun, Dong-Jae Liang, Chaoying Arana, Carlos Zhang, Bo Gao, Yajing Wakeland, Benjamin E. Dozmorov, Igor Zhou, Jinchun Kelly, Jennifer A. Lauwerys, Bernard R. Guthridge, Joel M. Olsen, Nancy J. Nath, Swapan K. Pasare, Chandrashekhar van Oers, Nicolai Gilkeson, Gary Tsao, Betty P. Gaffney, Patrick M. Gregersen, Peter K. James, Judith A. Zuo, Xiaoxia Karp, David R. Li, Quan-Zhen Wakeland, Edward K. Genome Biol Research BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis. BioMed Central 2020-11-19 /pmc/articles/PMC7677828/ /pubmed/33213505 http://dx.doi.org/10.1186/s13059-020-02184-z Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Raj, Prithvi Song, Ran Zhu, Honglin Riediger, Linley Jun, Dong-Jae Liang, Chaoying Arana, Carlos Zhang, Bo Gao, Yajing Wakeland, Benjamin E. Dozmorov, Igor Zhou, Jinchun Kelly, Jennifer A. Lauwerys, Bernard R. Guthridge, Joel M. Olsen, Nancy J. Nath, Swapan K. Pasare, Chandrashekhar van Oers, Nicolai Gilkeson, Gary Tsao, Betty P. Gaffney, Patrick M. Gregersen, Peter K. James, Judith A. Zuo, Xiaoxia Karp, David R. Li, Quan-Zhen Wakeland, Edward K. Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title | Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title_full | Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title_fullStr | Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title_full_unstemmed | Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title_short | Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
title_sort | deep sequencing reveals a dap1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677828/ https://www.ncbi.nlm.nih.gov/pubmed/33213505 http://dx.doi.org/10.1186/s13059-020-02184-z |
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