J. Lechner-Scott

Department of Neurology, John Hunter Hospital, Hunter New England Health

Author Of 2 Presentations

 Program
Genetics and Epigenetics Oral Presentation

PS08.03 - Deconvolution of epigenetic profiles reveals blood cell-specific pathways associated with early stage Multiple Sclerosis in the AusImmune Study

Speakers
Authors
Presentation Number
PS08.03
Presentation Topic
Genetics and Epigenetics
Lecture Time
13:15 - 13:27

Abstract

Background

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.

Objectives

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

Methods

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.

Results

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.

Conclusions

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.

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Gender Differences, Hormones and Sex Chromosomes Oral Presentation

PS12.04 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of relapse during pregnancy

Speakers
Authors
Presentation Number
PS12.04
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes
Lecture Time
10:00 - 10:12

Abstract

Background

Historically, disease activity diminished during pregnancy in women with relapsing-remitting MS. Today, women with high disease activity are more likely to attempt pregnancy due to the disease control that new therapies offer. But disease activity during pregnancy in the modern day remains understudied.

Objectives

Describe disease activity in a modern pregnancy cohort, grouped by preconception disease-modifying therapy (DMT) class; determine the predictors of relapse during pregnancy.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included. DMT were classed by low, moderate and high-efficacy. Annualized relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of relapse during pregnancy were determined using clustered logistic regression.

Results

We included 1640 pregnancies from 1452 women. DMT used in the year before conception were none (n=346), low (n=845), moderate (n=207) and high-efficacy (n=242). Most common DMT in each class was interferon-beta (n=597), fingolimod (n=147) and natalizumab (n=219) for low, moderate and high-efficacy respectively. Conception EDSS ≥2 was more common in higher efficacy DMT groups (high: 41.3%; moderate 28.5%; low 22.4%; none 20.2%). For low-efficacy and no DMT groups, ARR fell through pregnancy. ARR of the moderate-efficacy group increased in the 1st pregnancy trimester (0.55 [95% CI 0.36-0.80] vs 0.14 [95% CI 0.10-0.21] on low-efficacy), then decreased to a trough in the third. Conversely, ARR steadily increased throughout pregnancy for those on high-efficacy DMT (3rd trimester: 0.42 [95% CI 0.25-0.66] vs 0.12 [95% CI 0.07-0.19] on low-efficacy). Higher efficacy DMT groups were associated with higher ARR in the early postpartum period (high: 0.84 [95% CI 0.62-1.1]; moderate: 0.90 [95% CI 0.65-1.2]; low: 0.47 [95% CI 0.38-0.58]). Preconception use of high and moderate-efficacy DMT and higher preconception ARR were predictors of relapse in pregnancy. But, continuation of high-efficacy DMT into pregnancy was protective against relapse (odds ratio 0.80 [95% CI 0.68-0.94]). Age ≥35 years was associated with reduced odds of relapse.

Conclusions

Women with RRMS treated with moderate or high-efficacy DMT are at greater risk of relapse during pregnancy. Careful pregnancy management, and use of long-acting high-efficacy DMT preconception, or continuing natalizumab into pregnancy, may prevent relapse in pregnancy.

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