An international study led by researchers from Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) has cast new light on the underlying biological mechanisms causing differences in health risks, symptoms and outcomes between males and females, say the scientists.
The findings of the collaboration between the Berlin Institute of Health at Charité, Universitätsmedizin Berlin, and the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge were recently published in Nature Communications.
Using data from UK Biobank and the Fenland study, the team did in-depth analysis of the genetic links between ~6 000 proteins and hundreds of diseases in 56 000 men and women.
They found that for two-thirds of these proteins, their levels differed between males and females. Further examination revealed that only a very small fraction, around 100 proteins out of the 6 000 studied, had differences in the genetic ‘switches’ which control their levels, when compared between men and women.
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.
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, like 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 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 the study, data were categorised 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 categorisation was necessary, and data on gender identity were not reliably recoded meaning it could not be consistently used across all data.
Study details
Sex differences in the genetic regulation of the human plasma proteome
Mine Koprulu, Eleanor Wheeler, Nicola D. Kerrison et al.
Published in Nature Communications on 13 May 2025
Abstract
Mechanisms underlying sex differences in the development and prognosis of many diseases remain largely elusive. Here, we systematically investigated sex differences in the genetic regulation of plasma proteome (>5 800 protein targets) across two cohorts (30 307 females; 26 058 males). Plasma levels of two-thirds of protein targets differ significantly by sex. In contrast, genetic effects on protein targets are remarkably similar across sexes, with only 103 sex-differential protein quantitative loci (sd-pQTLs; for 2.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). A third of those show evidence of sexual discordance, i.e., effects observed in one sex only (n = 30) or opposite effect directions (n = 1 for CDH15). Phenome-wide analyses of 365 outcomes in UK Biobank did not provide evidence that the identified sd-pQTLs accounted for sex-differential disease risk. Our results demonstrate similarities in the genetic regulation of protein levels by sex with important implications for genetically-guided drug target discovery and validation.
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