Contributions
Abstract: EP1469
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Our understanding of relapsing-remitting MS (RRMS) has improved markedly, leading to several new therapies for RRMS patients; however, the pathology of progressive disease remains poorly understood. Epigenetics, such as DNA methylation, provide a logical interface for environmental factors to influence the genome. Our previous work identified two major differentially methylated regions (DMRs) at the HLA-DRB1 and RNF39 loci in CD4+T cells of RRMS patients. The aim of this study was to better understand the processes involved in secondary progressive MS (SPMS) by investigating the DNA methylation profiles of SPMS patients.
We performed an epigenome-wide association analysis of DNA methylation in CD4+ T cells from 24 SPMS patients and 24 healthy controls and a replication cohort of 12 SPMS patients and 12 healthy controls. DNA was bisulfite converted and hybridised to Illumina EPIC arrays. Data was analysed using a combination of R/Bioconductor and custom scripts.
Genome-wide methylation analysis revealed that the majority of differentially methylated sites (75%) in SPMS patients were hypermethylated. We did not identify the DMR at the HLA-DRB1 locus that we previously identified in the CD4+ T cells of RRMS patients. We did identify a DMR at the RNF39 locus as previously identified in RRMS patients. This DMR contains 7 of the sites contained in the RRMS cohort, which ranged from 10-13% differential methylation. In contrast to the hypermethylation seen in the RRMS cohort, the SPMS DMR is hypomethylated.
This data suggests that progression to SPMS results in increased DNA methylation. In addition, the differential methylation identified at HLA-DRB1 is only present in RRMS patients and not SPMS, suggesting this DMR may be unique to the earlier stage of disease. Finally, our data suggest RNF39 may switch from hypermethylated to hypomethylated in response to change in disease course. The biological relevance of this DMR can only be speculated on at this stage. RNF39 remains poorly characterized but is located in the major histocompatibility complex (MHC) class I region, suggestive of a role in immune system function. Consistent with this, RNF39 has been previously associated with other autoimmune conditions such as systemic lupus erythematosus and Becet's disease. Taken together, these results highlight the importance of epigenetic factors at the MHC region in MS.
Disclosure: Helmut Butzkueven: Compensation for steering committee, advisory board and consultancy fees from Biogen, Merck, Roche, Novartis, Teva, Oxford Pharamgenesis; research support from Novartis, Biogen, Merck, NHMRC Australia, MS Research Australia, UK MS Trust, Monash University; Prof. Jeannette Lechner-Scott´s institution receives non-directed funding, as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, Merck Serono, Teva, Roche, and Novartis Australia: All other authors have nothing to declare: This project was funded by Multiple Sclerosis Research Australia (MSRA). VEM is funding by fellowships from the MSRA and the Canadian Institutes of Health Research (CIHR). RAL is partially funded by a fellowship from the MSRA. KAS is funded by the Trish MS foundation and the MSRA.
Abstract: EP1469
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Our understanding of relapsing-remitting MS (RRMS) has improved markedly, leading to several new therapies for RRMS patients; however, the pathology of progressive disease remains poorly understood. Epigenetics, such as DNA methylation, provide a logical interface for environmental factors to influence the genome. Our previous work identified two major differentially methylated regions (DMRs) at the HLA-DRB1 and RNF39 loci in CD4+T cells of RRMS patients. The aim of this study was to better understand the processes involved in secondary progressive MS (SPMS) by investigating the DNA methylation profiles of SPMS patients.
We performed an epigenome-wide association analysis of DNA methylation in CD4+ T cells from 24 SPMS patients and 24 healthy controls and a replication cohort of 12 SPMS patients and 12 healthy controls. DNA was bisulfite converted and hybridised to Illumina EPIC arrays. Data was analysed using a combination of R/Bioconductor and custom scripts.
Genome-wide methylation analysis revealed that the majority of differentially methylated sites (75%) in SPMS patients were hypermethylated. We did not identify the DMR at the HLA-DRB1 locus that we previously identified in the CD4+ T cells of RRMS patients. We did identify a DMR at the RNF39 locus as previously identified in RRMS patients. This DMR contains 7 of the sites contained in the RRMS cohort, which ranged from 10-13% differential methylation. In contrast to the hypermethylation seen in the RRMS cohort, the SPMS DMR is hypomethylated.
This data suggests that progression to SPMS results in increased DNA methylation. In addition, the differential methylation identified at HLA-DRB1 is only present in RRMS patients and not SPMS, suggesting this DMR may be unique to the earlier stage of disease. Finally, our data suggest RNF39 may switch from hypermethylated to hypomethylated in response to change in disease course. The biological relevance of this DMR can only be speculated on at this stage. RNF39 remains poorly characterized but is located in the major histocompatibility complex (MHC) class I region, suggestive of a role in immune system function. Consistent with this, RNF39 has been previously associated with other autoimmune conditions such as systemic lupus erythematosus and Becet's disease. Taken together, these results highlight the importance of epigenetic factors at the MHC region in MS.
Disclosure: Helmut Butzkueven: Compensation for steering committee, advisory board and consultancy fees from Biogen, Merck, Roche, Novartis, Teva, Oxford Pharamgenesis; research support from Novartis, Biogen, Merck, NHMRC Australia, MS Research Australia, UK MS Trust, Monash University; Prof. Jeannette Lechner-Scott´s institution receives non-directed funding, as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, Merck Serono, Teva, Roche, and Novartis Australia: All other authors have nothing to declare: This project was funded by Multiple Sclerosis Research Australia (MSRA). VEM is funding by fellowships from the MSRA and the Canadian Institutes of Health Research (CIHR). RAL is partially funded by a fellowship from the MSRA. KAS is funded by the Trish MS foundation and the MSRA.