Genetic links to systemic sclerosis may differ by sex, new study finds

​Findings may help explain why SSc affects women and men differently
Written by Patricia Inácio, PhD | April 28, 2026

Some genetic factors linked to systemic sclerosis (SSc), also called scleroderma, may influence disease susceptibility differently in women and men, according to a new study.

Researchers say these findings may help explain why the disease is much more common in women, but often more severe in men. They also represent an early step toward precision medicine approaches that take these sex differences in SSc into account.

Overall, these findings “highlight the need for sex‑aware analytical approaches to uncover disease mechanisms that may be overlooked when both sexes are analysed together,” the researchers wrote.
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The study, “Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study,” was published in The Lancet Rheumatology.

​Researchers looked for genetic clues behind sex differences in SSc
SSc is an autoimmune disease marked by inflammation, blood vessel damage, and fibrosis, or scarring, in the skin and internal organs. Women are affected far more often than men, at about an 8-to-1 ratio, but men generally have a more severe disease course.

To better understand why, an international team of researchers assessed whether genetic factors in autosomes, the chromosomes that are not the X or Y sex chromosomes, differ by sex.

They analyzed genetic data from 10,653 people with SSc and 18,043 healthy people of European ancestry. In this study, sex was inferred from genetic data, which the authors noted may not always match sex assigned at birth or self-reported sex.

The analysis identified eight sex-specific genetic regions associated with SSc, called loci. One newly identified region near the BCL11A gene was associated with SSc only in male participants. In female participants, the researchers found two new SSc-associated regions: one in a section of the IRF4 gene that does not code for protein and another near the RPL3 and PDGFB genes. In addition, five previously known SSc-related genetic regions — mapped to IL12RB2, PXK, ARHGAP31, ULK3, and IRF8 — appeared to be female-specific.
Exploring further, the researchers then identified 39 possible genes that may be affected by these sex-specific genetic regions. The activity of five of those genes — IL12RB2, ARHGAP31, UBL7, CSK, and MPI — also differed by sex in blood samples from people with SSc. All showed higher activity in female patients than in male patients, except for ARHGAP31, which showed lower activity in female patients. The authors highlighted IL12RB2 as an especially important female-associated gene, as its activity was higher in immune cells called monocytes from female patients.

Findings point to immune pathways and possible treatment clues
Overall, the findings also strengthened evidence for the interferon pathway, an immune signaling system already thought to play a role in SSc. In an accompanying editorial, scientists in the U.S. said the female-associated findings involving IRF4 and IRF8 are “the first evidence of sex-biased autosomal genetic variation affecting the interferon pathway in systemic sclerosis,” and noted that they may support ongoing studies of interferon-targeting treatments, such as anifrolumab.

In a drug-repurposing analysis, the team identified two approved drugs as candidates for further study: fostamatinib, sold as Tavalisse for chronic immune thrombocytopenia and previously tested for rheumatoid arthritis, and dasatinib, a leukemia medicine that has been tested in SSc clinical trials. Still, the researchers cautioned that these drugs did not show enough benefit in SSc or rheumatoid arthritis, even though safety was acceptable.

“Considering all of these findings, revisiting clinical trial data with a sex-stratified framework could offer a more refined understanding of drug response than currently known, ultimately contributing to more tailored and effective therapeutic strategies for systemic sclerosis,” the researchers concluded.
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“The work of Rodriguez-Martin and colleagues,” the editorial concluded, “represents a crucial first step towards the rigorous sex-biased research required to achieve precise and equitable care for all patients with systemic sclerosis and related rheumatic diseases.”