Gene on X Chromosome May Be Reason Women at Higher Risk of MS, Study Says

Females of certain species — like humans and mice — have a known ability to produce more of the gene Kdm6a than males because it’s located on the X chromosome, of which females have two. Kdm6a is also quite active in immune system T-cells, a study found, and silencing it in a mice model of multiple sclerosis (MS) led to fewer disease symptoms, and lesser inflammation and damage to the spinal cord.

These findings may help to explain why women are more prone to MS and other autoimmune diseases than men, its researchers said. They also recommended more study into the diabetes medication metformin, which targets Kdm6a and might be the reason it shows an ability to modulate the immune system.

The study, “The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity,” was published in the Journal of Clinical investigation.

A woman’s risk of developing MS is about three times greater than a man’s, a difference that research suggests might be due to differences in sex hormones (estrogen and testosterone), in genes located on the X and Y sex chromosomes (which contain the DNA of a cell), or through a combination of the two.

Chromosomes inherited from a child’s parents determine its biological sex; women have two X chromosomes, and men have one X and one Y.

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Females, however, need only one active X chromosome to be healthy. Their bodies naturally deactivate one X chromosome to avoid producing excessive amounts of the genes that it carries. Nonetheless, some genes bypass such inactivation, resulting in their higher expression in women compared to men. (Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Researchers at the University of California, Los Angeles hypothesized that X chromosome genes that bypass being silenced might be related to the higher risk of autoimmune diseases seen in women.

They analyzed genes that were more expressed in immune T-cells of healthy controls (294 women and 205 men), as well as in female and male mice.

They found that women and the female mice had significantly more Kdm6a than their male counterparts. Kdm6a holds the instructions to produce a protein that can change the structure of DNA, and influence the genes activated by a given cell.

To test the role of Kdm6a in MS, scientists then inactivated this gene in T-cells — the immune cells that trigger the autoimmune response in MS — of mice in a disease model (experimental autoimmune encephalomyelitis, or EAE, model), and compared them to EAE mice with an active Kdm6a gene in their immune cells.

Mice without Kdm6a had fewer MS symptoms, lower numbers of immune cells attacking their spinal cords, and more healthy spinal nerve cells than mice with the active gene. These results suggested that silencing the Kdm6a gene has protective effects against MS.

Investigators also observed greater activity related to a healthy immune response in immune cells with inactive Kdm6a, and fewer genes related to nerve cell inflammation compared to what was seen in cells with active Kdm6a.

“Expression of Kdm6a from 2 alleles — the variants of a gene present in a cell — in women versus 1 allele in men may contribute to the higher susceptibility of women to MS,” the researchers wrote.

“Modulation of KDM6A in [T-]cells is a therapeutic target for MS and potentially other autoimmune diseases with a female preponderance,” they added.

Therapies that modulate Kdm6a might treat MS and other autoimmune diseases, the researchers also suggested.

Their study specifically mentioned metformin, an FDA-approved treatment for type 2 diabetes, as worthy of further investigation because it blocks the activity of the protein produced by the Kdm6a gene. “[I]n the context of this study, metformin could be viewed as a pharmacologic Kdm6a knockdown,” the team concluded.

Their work was also covered in a UCLA press release.