Biological differences between women and men led to variations in the appearance and progression of many diseases, which influenced diagnosis and response to treatments. These differences also affected the relationship between diseases, as they generated different combinations, risks, and patterns of joint appearance depending on sex. However, the biological mechanisms that explained these associations remained largely unexplored from a sex-differentiated perspective until now.
A new study led by the Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC), in collaboration with researchers from the University of Valencia and the Catholic University of Portugal, published in Communications Medicine (Nature Portfolio), integrated sex for the first time as a key variable in the analysis of molecular disease data. The work offered new biological hypotheses that explained why certain pathologies tended to co-occur more frequently in women or in men, which carried important implications for both research and clinical practice.
To carry out the analysis, the BSC scientific team used the computing power of the MareNostrum 5 supercomputer to process public data that showed how genes were activated, sourced from widely validated international consortia. In total, the team analyzed 8,906 patient samples corresponding to more than 100 diseases across 25 different tissues, separating the data according to biological sex. They observed that the same combination of diseases arose through totally different biological pathways depending on sex: while processes related to the immune system and metabolism predominated in women, mechanisms such as DNA and tissue repair stood out in men.
"Research historically used the male as the standard model, which caused diagnostic biases and less effective treatments for women," explained Alfonso Valencia, ICREA professor, director of the Life Sciences Department at the BSC, and senior author of the study. "Our results reinforced the need to systematically analyze women and men separately to move toward a more precise and equitable science, integrating sex as a fundamental biological variable."
Until now, most studies that attempted to explain at a molecular level why certain diseases co-occurred more frequently than expected by chance did so without considering the role of sex. By analyzing the data separately for women and men, the research team identified biological mechanisms suggesting that risk-reduction strategies should be sex-specific, as a treatment that was effective for a man was not necessarily effective for a woman.
"We observed, for example, that type 2 diabetes and some types of cancer showed different associations in men and women, mediated by different biological mechanisms," noted Jon Sánchez-Valle, researcher at the BSC and first author of the study. "These data pointed to trends that helped generate new hypotheses about how these diseases related to each other, but it was necessary to confirm them in other populations."
Toward a precision medicine with a sex and gender perspective
The study also explored the relationship between disease co-occurrence and drug use, noting that some commonly used medications—such as metformin, certain chemotherapies, or bronchodilators—presented different associations depending on sex. These results suggested that the same drug modulated the risk of associated diseases differently in women and men.
"We detected that the use of metformin was associated with different patterns in men and women regarding certain diseases like liver cancer, which related to hormonal and metabolic differences," indicated Sánchez-Valle. "Understanding these mechanisms at a molecular level helped us design more precise clinical studies and rethink drug repurposing strategies."
If the efficacy and side effects of some treatments depended on the patient's sex, integrating this variable from the early stages of research contributed to preventing adverse effects and advancing toward a precision medicine better adjusted to the biological reality of each person.
"Understanding from a biological standpoint why these differences occurred allowed us to identify new therapeutic targets and move toward more appropriate treatments for each condition," added Sánchez-Valle. "This work opened the door to a precision medicine that no longer assumed that what worked for men necessarily worked for women."
By demonstrating that diseases and their relationships were not the same in women and men, the researchers concluded, the need to integrate the sex variable to overcome the historical biases that still persisted in public health became evident. Only in this way, they said, was it possible to move toward a fairer precision medicine that guaranteed each patient received the treatment most appropriate to their biological and social reality.
This study was part of the intersection of two strategic research lines at the BSC: the analysis of sex and gender biases in biomedicine and artificial intelligence, promoted through the Bioinfo4Women program; and the study of comorbidity and disease relationships within European and national projects (COMMUTE and HEALED).
