Study may help explain protective effects of pregnancy in MS

A new study of women with multiple sclerosis (MS) who had previously given birth may have identified one of the mechanisms behind the lasting protective effects of pregnancy seen in MS patients.

Patients who’d had children were found to have a number of differences in methylation, a type of DNA modification, compared with their counterparts who had never been pregnant.

Many of the affected genes were related to nerve cell development and function.

“Based on these findings, we believe that pregnancy-induced differences in DNA methylation could underlie the long-term protective effect of pregnancy in women with MS,” Pia Campagna, a PhD student at Monash University, in Australia, and the study’s first author, said in a university press release.

The findings were published in Clinical Epigenetics in a study titled, “Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis.”

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MS is most commonly diagnosed in women of reproductive age, between the ages of about 20-40. As such, understanding how pregnancy influences disease progression is critical for providing these patients with proper care.

While the relationship between pregnancy and MS is complex, some data indicate that having babies could be protective in the long term. Previous studies have found that a history of childbirth can delay MS onset and progression.

The mechanisms by which pregnancy might offer protection in MS haven’t been fully established, but some studies point to epigenetics, specifically DNA methylation, as a contributing factor. Epigenetics is a type of reversible modification that doesn’t change the actual DNA sequence, the way a mutation would, but instead affects the way the DNA sequence is read.

Methylation is a type of epigenetic modification. It involves chemical reactions that add a molecule called a methyl group to DNA, which can activate or suppress gene activity.

It is thought that in pregnancy, methylation might influence the activity of genes affecting immune and brain function, in turn influencing disease course. However, this potential mechanism has not been comprehensively studied.

Now, a team of scientists, led by researchers at Monash, analyzed blood samples from MS patients to look for any epigenetic changes that could influence disease progression in the long term.

Their study involved 192 women with relapsing MS. Half had never been pregnant and thus were identified as nulliparous, while the other 96 women had given birth and were characterized as parous.

Women in the two groups were matched in terms of age and disease severity. Among those who had given birth, at the time of blood collection, it had been a median of 16.7 years since their last conception.

The analysis revealed 2,965 spots on DNA with a different methylation status between parous and nulliparous women, many of which overlapped with previous findings.

Specifically, changes were observed in genes related to neural plasticity, or the process through which the brain rewires itself in response to new information, as well as neural growth and development. Often, these regions saw hypermethylation, or increased methylation, in the parous group.

“Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes,” the researchers wrote.

We believe that pregnancy-induced differences in DNA methylation could underlie the long-term protective effect of pregnancy in women with MS.

Two DNA regions in particular seemed to hold a number of places with altered methylation. These regions corresponded to the ZNF577 and TMC8 genes. More work is needed to better understand the role of these genes in pregnancy and MS, the team noted.

Further analyses found methylation differences specifically in certain types of T-cells, a type of immune cell that has been implicated in MS disease processes.

Methylation analyses also can be used to evaluate disparities between a person’s chronological age and their biological or cellular one. Essentially, methylation changes at certain sites in the genome are known to change over time and can be used to monitor how fast a person’s cells are aging.

Women who had been pregnant showed signs of slower biological aging than their nulliparous counterparts, similar to previous findings in the general population.

“We found significantly different levels of DNA methylation at genes associated with neural plasticity pathways at a median of 16.7 years after conception,” Campagna said, adding, “We also observed slower biological ageing in parous women which is consistent with previous research in healthy women.”

While these findings require validation in a larger group of patients, they overall suggest that methylation changes may contribute to different MS outcomes in women who have given birth.

The researchers are now seeking to confirm the findings in a long-term study of women with or without MS who are planning a pregnancy, which will be conducted in partnership with Roche. Immune and genetic changes will be analyzed during and after pregnancy to better understand how they may protect against disability progression in MS.

“This could lead to the identification [of] novel therapeutic targets,” the researchers wrote.