Author Of 1 Presentation
PS08.03 - Deconvolution of epigenetic profiles reveals blood cell-specific pathways associated with early stage Multiple Sclerosis in the AusImmune Study
Genomic DNA methylation is a modifiable epigenetic mechanism that exhibits wide-spread variation among blood cell types. Methylation can influence disease phenotypes via modulating the effects of genetic and environmental factors on gene expression. Changes in methylation at the human leukocyte antigen gene (HLA-DRB1) have been previously associated with multiple sclerosis (MS) in both T lymphocytes and monocytes. This association is influenced by the well-established MS haplotype at this locus.
To further characterise the cell-specific methylation profiles of MS by performing an epigenome-wide association study (EWAS) incorporating a statistical deconvolution of whole blood data
This was a case-control design involving subjects from the AusImmune Study. Specifically included were, 221 MS patients at first demyelination diagnosis and 468 population-based controls matched for age, sex and residential location. DNA methylation derived from whole blood was measured using Illumina EPIC arrays. EWAS analysis was performed using the ChAMP program. Cell deconvolution analysis was performed using the CellDMC function of the EpiDISH program . This method adjusts methylation levels by variation in blood cell proportions among subjects and can effectively estimate cell-specific methylation profiles without the need to do cell sorting. Gene set enrichment analysis (GSEA) was performed using the ToppGene program. All tests were assessed for statistical significance using a false discovery rate (FDR) of 0.05.
The top differentially methylated region (DMR) was HLA-DRB1, which included both hypo and hyper methylation loci (PFDR<0.05). The underlying HLA-DRB1 haplotype was strongly associated with these DMRs. Deconvolution analyses showed that the HLA-DRB1 signal specifically originated from T cells and monocytes, which is consistent with previous findings. Interestingly, cell-specific GSEA revealed associations with pathways related to axonal guidance signalling, specifically in T cells, natural killer (NK) cells, and B cells. In particular, epigenetic variation in the Netrin-1 signalling pathway in both NK and B cells was associated with MS in this cohort (PFDR<0.05). Netrin‐1, is an axon guidance protein that reduces serum levels of pro-inflammatory mediators and stabilizes the blood-brain barrier limiting the entrance of immune cells into the central nervous system. These pathways were not detected in whole blood methylation analyses, highlighting the importance of the cellular deconvolution approach.
These results provide provisional evidence that epigenetic variation in axonal signalling pathways is associated with early-stage MS in a cell-dependent manner. If validated, these findings might help guide future efforts in epigenetic medicine for MS.
Author Of 1 Presentation
P0104 - Long term disability trajectories in multiple sclerosis: a group-based trajectory analysis of the AusLong cohort (ID 1920)
Understanding progression of disability in multiple sclerosis (MS) is essential to design preventive and therapeutic strategies.
We analyzed data from the Ausimmune Longitudinal (AusLong) Study to investigate the existing heterogeneity in long-term disability accumulation in a prospective cohort of People with MS (PwMS) followed over 10 years from the date of their first clinical diagnosis (FCD) and identify clinical and demographic factors associated with these trajectories.
We used a group-based trajectory model (GBTM) to measure the heterogeneity in the disability trajectories based on Expanded Disability Status Scale (EDSS) in a prospective cohort of 263 participants followed from FCD.
We identified three distinct clinically meaningful disability trajectories: no or mild, moderate and severe disability trajectories. Those in the minimal disability trajectory did not show any appreciable progression of disability (median EDSS ~ 1 at 10-year review), those in moderate and severe disability trajectories experienced disability worsening (median EDSS~ 2.5 and 6, respectively). The relative probability of being in a worsening disability trajectory was higher for older age at onset, those experiencing a higher number of relapses within five-year post FCD and those having a shorter interval between the first two attacks. High annual relapse rate was associated with an upward shift in moderate disability trajectory, whereas non-smoking status was associated with reducing the EDSS score in minimal and severe disability trajectories.
Those at highest risk of rapid disability progression can be identified based on their early clinical information with potential therapeutic implications.