A new international study has revealed that most protein-level differences between men and women aren’t due to genetics alone.
A major international study has uncovered new insights into why men and women often face different health risks, symptoms, and outcomes. Led by researchers at Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI), the study reveals key biological differences that may help explain these variations.
In collaboration with the Berlin Institute of Health at Charité, Universitätsmedizin Berlin, and the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the research was published in Nature Communications. By analyzing data from the UK Biobank and the Fenland Study, the team examined genetic links between approximately 6,000 proteins and hundreds of diseases across 56,000 men and women.
The team found that two-thirds of the proteins showed different levels in males and females. But when the researchers looked deeper into the genetic “switches” that control these protein levels, they discovered that only a very small number, roughly 100 proteins, were actually regulated differently based on sex.
Implications for Precision Medicine
These findings, which may have implications for drug development, indicate that while there are differences between the sexes in relation to how much they express certain proteins, what’s causing these differences isn’t solely down to differences in their genetics.
Instead, the authors highlight the importance of looking beyond genetics – and other medical factors such as hormones – when comparing health risks and outcomes between males and females. Their findings indicate that non-medical factors such as where people work and live, their education, financial situation, access to resources, as well as their lifestyle, also contribute to the health differences experiences between the sexes and so should be explored further and considered more when exploring sex differences in health.
Calls for a More Inclusive Healthcare Model
Mine Koprulu, lead author of the study and a postdoctoral researcher at Queen Mary’s PHURI, said: “For the first time in history, we are able to study human biology at this level of detail—across genes, proteins, and more. This is the largest study to date exploring the similarities and differences in how our genetic code regulates blood protein levels between sexes. Our findings highlight the need to better understand the factors that impact health differences — at the genetic level and beyond— to create more tailored and equitable healthcare for everyone.”
Professor Claudia Langenberg, Director of the PHURI at Queen Mary and Professor of Computational Medicine at the Berlin Institute of Health at Charité, Germany, said: “Drug development pipelines increasingly incorporate information on genetic differences in protein levels and function and this has led to large investment in human cohorts, such as UK Biobank. From this perspective, better understanding of population differences in the regulation of proteins, such as those between males and females, is essential to guide precision medicine approaches and identify where one size may not fit all. Our results clearly show that with very few exceptions, protein regulating genetic variants identified so far behave in a very similar way in males and females. This provides evidence for an important implicit assumption – that insights arising from studying these variants apply to both sexes.”
In this study, data was categorized as male or female based on chromosomal information (XX or XY). The authors acknowledge that chromosomal information does not always align with an individual’s gender identity. However, for the purposes of this study (genetic and protein-level scientific analyses), this categorization was necessary, and data on gender identity was not reliably recoded, meaning it could not be consistently used across all data.
Reference: “Sex differences in the genetic regulation of the human plasma proteome” by Mine Koprulu, Eleanor Wheeler, Nicola D. Kerrison, Spiros Denaxas, Julia Carrasco-Zanini, Chloe M. Orkin, Harry Hemingway, Nicholas J. Wareham, Maik Pietzner and Claudia Langenberg, 13 May 2025, Nature Communications.
DOI: 10.1038/s41467-025-59034-4
Funding: Medical Research Council, Medical Research Council, Gates Cambridge Trust, Health Data Research UK, NIHR Biomedical Research Centre, British Heart Foundation
Conflicts of interest: Eleanor Wheeler is now an employee of AstraZeneca. The remaining authors declare no competing interests.
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