New Research Unveils Key Health Differences Between Men and Women

A groundbreaking international study spearheaded by researchers at Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) has unveiled remarkable insights into the biological mechanisms governing health disparities between males and females. Published in the prestigious journal Nature Communications, this comprehensive investigation leverages large-scale genetic and proteomic data sets from UK Biobank and the Fenland Study, illuminating the nuanced interplay of genetics and physiology underlying sex-specific health risks, symptoms, and disease outcomes.

Delving deep into the human plasma proteome, the research team analyzed approximately 6,000 proteins across a cohort of 56,000 individuals, evenly distributed between males and females. This extensive dataset allowed the scientists to conduct one of the most detailed examinations to date of how genetic factors regulate protein levels in blood and how these regulatory mechanisms diverge or converge between the sexes. Their findings demonstrate that while two-thirds of these proteins exhibit differences in expression levels between men and women, the genetic variants controlling these protein levels show near-universal similarity across sexes, with only about 100 proteins displaying sex-specific genetic regulation.

This pivotal discovery challenges traditional assumptions that genetic differences entirely drive the observed sex-based disparities in many health conditions. Rather, it underscores the complexity of protein expression control—a multifactorial process influenced by genetics as well as a constellation of non-genetic factors. The researchers emphasize that biology beyond the genome, such as epigenetic modulation, hormonal milieu, and environmental context, intricately shapes the proteomic landscape in males and females, thereby influencing disease susceptibility and therapeutic responses.

Critically, the study highlights the substantial role that social determinants of health play in modulating biological differences across sexes. Factors like occupational exposures, residential environments, socioeconomic status, education, and lifestyle habits emerge as vital contributors that intertwine with biological processes to affect health outcomes. This broader perspective advocates for a more holistic approach in biomedical research and drug development—one that transcends genomics to also integrate socio-environmental influences to foster precision medicine that is truly inclusive and equitable.

At the heart of this research lies a methodological innovation in parsing male-female differences through chromosomal information (XX for females and XY for males), capitalizing on the wealth of genotypic and transcriptomic data available. Although chromosomal sex does not capture the full spectrum of gender identity, the decision reflects the necessity to utilize biologically defined categories for rigor in genetic and proteomic analyses. This caveat is openly acknowledged by the authors, calling for future studies to refine and expand methodologies to inclusively represent gender diversity in biomedical research.

Mine Koprulu, the study’s lead author and a postdoctoral researcher at PHURI, remarks on the unprecedented resolution this research achieves in understanding human biology. She notes that this large-scale investigation traverses multiple layers from genes to proteins, advancing our comprehension of how the human genetic code orchestrates protein abundance distinctly in males and females. Koprulu stresses the importance of integrating genetic and extragenetic factors to delineate the pathways leading to sex-specific health risks, ultimately underpinning the goal of delivering healthcare tailored more precisely to individual needs.

Professor Claudia Langenberg, Director of PHURI and a computational medicine expert affiliated with the Berlin Institute of Health at Charité, emphasizes the implications for drug development pipelines that increasingly rely on genetic insights. She explains that the widespread assumption of uniform protein regulatory genetic variants across sexes largely holds true, facilitating the translation of human genetic findings into therapeutic targets applicable to both males and females. Nevertheless, the rare exceptions identified warrant further investigation to ensure that precision medicine strategies do not inadvertently neglect sex-specific biological nuances.

The study exemplifies an integrative observational research design, harnessing robust population cohorts to dissect the genetic architecture underlying protein expression. UK Biobank and the Fenland Study offer rich phenotypic and genotypic data enabling sophisticated genetic association analyses. By correlating single nucleotide polymorphisms (SNPs) with plasma protein levels stratified by sex, the team illuminated both shared and distinct molecular regulatory mechanisms, providing a foundational resource for future functional studies.

In addition to identifying sex-independent genetic variants influencing proteomic profiles, the research throws spotlight onto environmental and lifestyle contributors that intersect with genetic predisposition to mold sex-dimorphic disease patterns. This paradigm shift calls for a multidisciplinary research agenda, scrutinizing how everyday exposures and social conditions interface with biology to yield complex health trajectories divergent by sex.

The findings bear particular relevance in the context of complex diseases such as cardiovascular conditions, autoimmune disorders, and metabolic syndromes, which frequently show marked sex differences in incidence and progression. Understanding proteomic regulation at this granular level offers pathways to discover novel biomarkers and refine therapeutic interventions, ensuring that sex is factored conscientiously into clinical decision-making and drug design.

Moreover, the study’s methodological transparency and candid discussion of limitations—especially regarding the binary chromosomal sex classification and its implications—set a commendable standard for future inquiries into sex and gender in biomedical science. This openness will likely inspire closer scrutiny of how sex and gender variables are operationalized in research, fostering inclusivity and accuracy.

In sum, this landmark study orchestrates a sophisticated symphony of genetics, proteomics, and environmental health sciences to unravel the biological underpinnings of sex differences in human health. By revealing that genetic control of protein expression is largely conserved between males and females, yet expression levels vary due to non-genetic factors, it redefines our approach to precision medicine and underscores the necessity of integrating social determinants into biological research frameworks.

As we move toward an era of increasingly personalized healthcare, insights gleaned from this work highlight that precision cannot be achieved by genetics alone. A broader, more intersectional framework that blends biology with the lived realities of individuals is indispensable to charting the future of equitable and effective medical interventions that transcend sex disparities.

Subject of Research: People

Article Title: Mine Koprulu, et al. “Sex differences in the genetic regulation of the human plasma proteome.”

News Publication Date: 13-May-2025

Web References:

https://www.nature.com/articles/s41467-025-59034-4
https://www.qmul.ac.uk/phuri/
https://www.ukbiobank.ac.uk/
https://studies.mrc-epid.cam.ac.uk/fenland

References:
DOI: 10.1038/s41467-025-59034-4

Keywords: Protein expression, Sex chromosomes, Risk factors, Disease susceptibility, Genetic analysis, Human genetics

Tags: biological mechanisms of healthcomprehensive examination of health datagenetic factors in healthhealth disparities between men and womenhealth outcomes based on sexnuanced interplay of genetics and physiologyproteomic data analysissex differences in protein levelssex-specific genetic regulation of proteinssex-specific health riskstraditional assumptions in health researchUK Biobank study insights