Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: Identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI

Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylatio...

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Published in	Journal of autoimmunity Vol. 96; pp. 147 - 157
Main Authors	Joseph, Stancy, George, Nysia I., Green-Knox, Bridgett, Treadwell, Edward L., Word, Beverly, Yim, Sarah, Lyn-Cook, Beverly
Format	Journal Article
Language	English
Published	England Elsevier Ltd 01.01.2019
Subjects	African Americans DNA Methylation Epigenesis, Genetic Epigenome - genetics Ethnicity European Continental Ancestry Group Female Humans Interferon Interferon Type I - genetics Interferon Type I - metabolism Leukocytes, Mononuclear - physiology Lupus Lupus Erythematosus, Systemic - epidemiology Lupus Erythematosus, Systemic - genetics Lupus Erythematosus, Systemic - immunology Male Middle Aged Signal Transduction SLEDAI Transcriptome United States - epidemiology United States Lupus DNA methylation SLEDAI Ethnicity Interferon
Online Access	Get full text
ISSN	0896-8411 1095-9157 1095-9157
DOI	10.1016/j.jaut.2018.09.007

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Abstract	Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis. •Systemic lupus erythematosus is characterized by DNA methylation signature.•African Americans (AA) have a robust DNA methylation profile compared to European Americans (EA).•Patients with SLEDAI>6 scores have robust DNA methylation profile compared to patients with SLEDAI≤6 scores.•Interferon-related genes have a robust hypomethylation pattern in AA patients and patients with SLEDAI>6 score.
AbstractList	Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis. •Systemic lupus erythematosus is characterized by DNA methylation signature.•African Americans (AA) have a robust DNA methylation profile compared to European Americans (EA).•Patients with SLEDAI>6 scores have robust DNA methylation profile compared to patients with SLEDAI≤6 scores.•Interferon-related genes have a robust hypomethylation pattern in AA patients and patients with SLEDAI>6 score. Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis.Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis. Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of antinuclear antibodies. DNA methylation plays an important role in the pathogenesis of lupus. We have performed an epigenome-wide DNA methylation study in lupus and healthy control (non-lupus) subjects to identify epigenetic patterns in lupus characterized ethnicity and SLE disease activity index (SLEDAI). A total of fifty-seven lupus patients (39 African American (AA) and 18 European American (EA)) and 33 healthy controls (17 AA and 16 EA) were studied. Differential DNA methylation between lupus patients and controls was assessed for approximately 485,000 CpG sites across the genome. We identified 41 differentially methylated sites (associated with 30 genes) between lupus and control s subjects, 85% of which were hypomethylated. Significant hypomethylation of differentially methylated sites was associated with several interferon-related genes, including MX1, IFI44L, PARP9, DT3XL, IFIT1, IFI44, RSAD2, PLSCR1, and IRF7. Several of these associated genes were also hypomethylated in comparisons between AA lupus and AA non-lupus subjects and between lupus patients with SLEDAI>6 and non-lupus subjects. Our analysis of gene expression data through RT-PCR confirmed these findings. Thus, the results indicate epigenetics susceptibility in lupus, which may be associated with SLEDAI score and ethnicity. In addition, our findings support the importance of the Type 1 interferon pathway in lupus pathogenesis.
Author	Treadwell, Edward L. George, Nysia I. Joseph, Stancy Green-Knox, Bridgett Lyn-Cook, Beverly Yim, Sarah Word, Beverly
Author_xml	– sequence: 1 givenname: Stancy surname: Joseph fullname: Joseph, Stancy organization: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA – sequence: 2 givenname: Nysia I. surname: George fullname: George, Nysia I. organization: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA – sequence: 3 givenname: Bridgett surname: Green-Knox fullname: Green-Knox, Bridgett organization: Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA – sequence: 4 givenname: Edward L. surname: Treadwell fullname: Treadwell, Edward L. organization: East Carolina Brody School of Medicine, Greenville, NC, USA – sequence: 5 givenname: Beverly surname: Word fullname: Word, Beverly organization: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA – sequence: 6 givenname: Sarah surname: Yim fullname: Yim, Sarah organization: Center for Drug Evaluation, White Oak, MD, USA – sequence: 7 givenname: Beverly surname: Lyn-Cook fullname: Lyn-Cook, Beverly email: Beverly.lyn-cook@fda.hhs.gov organization: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30301579$$D View this record in MEDLINE/PubMed
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Keywords	Lupus DNA methylation SLEDAI Ethnicity Interferon
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Snippet	Systemic lupus erythematosus (SLE or lupus) is a heterogeneous autoimmune disease characterized by the involvement of multiple organs and the production of...
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SubjectTerms	African Americans DNA Methylation Epigenesis, Genetic Epigenome - genetics Ethnicity European Continental Ancestry Group Female Humans Interferon Interferon Type I - genetics Interferon Type I - metabolism Leukocytes, Mononuclear - physiology Lupus Lupus Erythematosus, Systemic - epidemiology Lupus Erythematosus, Systemic - genetics Lupus Erythematosus, Systemic - immunology Male Middle Aged Signal Transduction SLEDAI Transcriptome United States - epidemiology
Title	Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: Identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI
URI	https://www.clinicalkey.com/#!/content/1-s2.0-S0896841118303524 https://dx.doi.org/10.1016/j.jaut.2018.09.007 https://www.ncbi.nlm.nih.gov/pubmed/30301579 https://www.proquest.com/docview/2117820401
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