Study Reveals Genetic Factors Behind Higher Autoimmune Disease Rates in Women

Researchers from the Garvan Institute of Medical Research and UNSW Sydney have identified over 1,000 genetic switches that differ between male and female immune cells, shedding light on why autoimmune diseases, such as lupus, disproportionately affect women.

Autoimmune diseases occur when the immune system mistakenly attacks the body’s own healthy tissues. Lupus exemplifies this trend, affecting as many as nine women for every one man. Despite the significant prevalence, the genetic underpinnings of this disparity have not been well understood until now.

The findings, published in The American Journal of Human Genetics, illustrate that the immune response can manifest differently in males and females, emphasizing the necessity for including both sexes in medical research—a practice that has historically favored male groups. “Our findings show that the immune system needs to be studied with sex in mind. Even though we know men’s and women’s immune systems differ, many studies still overlook these differences,” said Dr. Seyhan Yazar, the study’s first author.

Advancements in Immune Cell Research

Previous studies on gender differences in immune systems were limited due to technology constraints, often relying on traditional blood analysis methods that fail to capture variations among specific cell types. However, advancements in single-cell technologies enabled the research team to analyze immune cells at an unprecedented scale.

The researchers sequenced more than 1.25 million peripheral blood mononuclear cells from nearly 1,000 healthy participants as part of the OneK1K cohort project, designed to explore the genetic factors influencing immune cell behavior across a vast population.

In their analysis, the researchers found distinct differences: males had a higher proportion of monocytes, which respond quickly to threats, while their gene activity focused on cell maintenance and protein production. Females exhibited greater numbers of B cells and regulatory T cells, with heightened genetic activity related to inflammatory pathways. “While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases,” explained co-senior author Dr. Sara Ballouz, a Senior Lecturer at UNSW.

Genetic Insights into Autoimmune Disease

The study pinpointed specific genetic switches that function differently in males and females, termed “expression quantitative trait loci,” which regulate gene activation and suppression levels. Contrary to assumptions that differences stem primarily from X and Y sex chromosomes, the identified switches were largely located on autosomes, the non-sex chromosomes shared by both sexes.

Among the significant findings, the researchers linked variants that promote female-biased expression of genes associated with systemic lupus erythematosus, potentially explaining the higher incidence of this condition in women.

“This is the first time we have shown that these differences occur at the genetic control level, providing a new layer of insight into human immunity,” Dr. Ballouz remarked. “Having shown that female-biased genes are heavily enriched in inflammatory pathways, we now have another biological rationale for why the immune system can more easily mistakenly attack the body’s own tissues in women.”

Implications for Autoimmune Treatments

The implications of the research extend to treatment strategies for autoimmune conditions, suggesting that individualized therapies could be developed rather than broadly suppressing immune activity. Current treatments often do not work uniformly across different patient demographics.

Dr. Yazar emphasized the need for more personalized approaches: “Our findings add strong evidence that female and male autoimmune diseases may not be the same, and the way we should treat them may not necessarily be the same.” Professor Joseph Powell, co-senior author and Director of Garvan’s Translational Genomics Program, asserted, “If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables.”