Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis

Moira C. Graves, Miles C. Benton, R. A. Lea, Frances M. Boyle, L. Tajouri, D. Macartney-Coxson, Rodney J. Scott, Jeannette Lechner-Scott

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Abstract

Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10-3). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

Original languageEnglish
Pages (from-to)1033-1041
Number of pages9
JournalMultiple Sclerosis
Volume20
Issue number8
DOIs
Publication statusPublished - 2014

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HLA-DRB1 Chains
Methylation
Multiple Sclerosis
T-Lymphocytes
DNA Methylation
Relapsing-Remitting Multiple Sclerosis
CpG Islands
Environmental Exposure
Epigenomics
Genome
Pathology

Cite this

Graves, M. C., Benton, M. C., Lea, R. A., Boyle, F. M., Tajouri, L., Macartney-Coxson, D., ... Lechner-Scott, J. (2014). Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. Multiple Sclerosis, 20(8), 1033-1041. https://doi.org/10.1177/1352458513516529
Graves, Moira C. ; Benton, Miles C. ; Lea, R. A. ; Boyle, Frances M. ; Tajouri, L. ; Macartney-Coxson, D. ; Scott, Rodney J. ; Lechner-Scott, Jeannette. / Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. In: Multiple Sclerosis. 2014 ; Vol. 20, No. 8. pp. 1033-1041.
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abstract = "Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10-3). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.",
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Graves, MC, Benton, MC, Lea, RA, Boyle, FM, Tajouri, L, Macartney-Coxson, D, Scott, RJ & Lechner-Scott, J 2014, 'Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis' Multiple Sclerosis, vol. 20, no. 8, pp. 1033-1041. https://doi.org/10.1177/1352458513516529

Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. / Graves, Moira C.; Benton, Miles C.; Lea, R. A.; Boyle, Frances M.; Tajouri, L.; Macartney-Coxson, D.; Scott, Rodney J.; Lechner-Scott, Jeannette.

In: Multiple Sclerosis, Vol. 20, No. 8, 2014, p. 1033-1041.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis

AU - Graves, Moira C.

AU - Benton, Miles C.

AU - Lea, R. A.

AU - Boyle, Frances M.

AU - Tajouri, L.

AU - Macartney-Coxson, D.

AU - Scott, Rodney J.

AU - Lechner-Scott, Jeannette

PY - 2014

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N2 - Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10-3). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

AB - Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10-3). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

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