High Lupus Rates Among Women Appear to Be Unrelated to Hormones

Researchers have uncovered genetic differences explaining why autoimmune diseases, such as systemic lupus erythematosus, affect women more than men. And opposed to what earlier research suggested, the mechanisms are unrelated to sex hormones.

The findings indicate that it may be crucial for scientists to study male and female disease separately.

The study, “A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases,” was published in the journal Nature Immunology.

Extensive work in mapping gene-activity differences led the team down a path that converged on a factor called VGLL3, which controls a host of genes in an immune network more likely to operate in women.

“We found a completely new angle,” Johann Gudjonsson, MD, PhD, University of Michigan Health System assistant professor of dermatology, said in a news release. He was referring to the fact that most studies exploring sex differences in autoimmune diseases focus on the impact of sex hormones.

“Our team identified a gene expression difference between the sexes that is associated with susceptibility to autoimmune disease,” said Gudjonsson, the study’s senior investigator.

In their daily work, the research team focuses on autoimmune conditions affecting the skin, such as lupus and psoriasis. To gain an idea of immune differences between men and women, the researchers first analyzed gene activity in skin samples taken from 31 women and 51 men — all healthy.

Although skin seemingly differs little between the sexes, the team found differences in activity levels in an astonishing 661 genes.

Interestingly, many of the genes had known roles in immune responses, and gene analyses had suggested they posed autoimmune-disease risk. Ultimately, the team found that the transcription factor VGLL3 controlled most of the genes. A transcription factor is a molecule that binds to DNA to activate a gene.

While VGLL3 was more likely to trigger gene expression linked to disease in women, it was also active in men with autoimmune conditions. Naturally, the team wondered whether hormonal difference might influence VGLL3 — but the answer was no.

“We found no evidence of involvement of estrogen or testosterone in the immune differences we observed between women and men,” Gudjonsson said. “Identifying a separate regulatory mechanism could be a huge advance in gender-focused autoimmune research.

“Learning more about these disease processes in each gender will provide opportunities for therapeutic interventions we did not imagine before, including both prevention and treatment,” he concluded.