Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis

Maria Pia Campagna; Alexandre Xavier; Jim Stankovich; Vicki E Maltby; Mark Slee; Wei Z Yeh; Trevor Kilpatrick; Rodney J Scott; Helmut Butzkueven; Jeannette Lechner-Scott; Rodney A Lea; Vilija G Jokubaitis

doi:10.1186/s13148-023-01438-4

Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis

Clin Epigenetics. 2023 Feb 10;15(1):20. doi: 10.1186/s13148-023-01438-4.

Authors

Maria Pia Campagna¹, Alexandre Xavier^{2

3}, Jim Stankovich⁴, Vicki E Maltby^{3

5

6}, Mark Slee⁷, Wei Z Yeh^{4

8}, Trevor Kilpatrick^{9

10}, Rodney J Scott^{2

3}, Helmut Butzkueven^{4

8}, Jeannette Lechner-Scott^#^{3

5

6}, Rodney A Lea^#^{3

11}, Vilija G Jokubaitis^#^{4

8

9

10}

Affiliations

¹ Department of Neuroscience, Monash University, Melbourne, VIC, Australia. maria.campagna@monash.edu.
² School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
³ Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
⁴ Department of Neuroscience, Monash University, Melbourne, VIC, Australia.
⁵ School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
⁶ Neurology Department, John Hunter Hospital, Hunter New England, Newcastle, NSW, Australia.
⁷ College of Medicine and Public Health, Flinders University, Adelaide, Australia.
⁸ Neurology Department, Alfred Health, Melbourne, VIC, Australia.
⁹ Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
¹⁰ Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹¹ Queensland University of Technology, Brisbane, QLD, Australia.

^# Contributed equally.

Abstract

Background: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.

Results: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4⁺ and eight in CD8⁺ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.

Conclusion: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.

Keywords: Birth; Epigenetics; Neurodegeneration; Neuroplasticity; Pregnancy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / metabolism
DNA Methylation*
Female
Humans
Membrane Proteins / genetics
Multiple Sclerosis* / genetics
Multiple Sclerosis* / metabolism
Neuronal Plasticity
Parity
Pregnancy

Substances

TMC8 protein, human
Membrane Proteins