A new study reveals that over 100 genes are expressed differently between males and females, influencing disease susceptibility and treatment response across conditions like cancer, autoimmune disorders, and cardiovascular illness, with implications for sex-specific medicine.
How Gene Expression Differences Between Sexes Reshape Disease Understanding
Published this week in a leading genomics journal, researchers analyzed tissue samples from multiple organs in healthy adult donors and found consistent, biologically significant differences in the expression of 102 genes between males and females. These genes are not limited to reproductive tissues but are active in the liver, brain, heart, and immune system, affecting processes such as inflammation, drug metabolism, and cellular repair. The findings underscore that biological sex is a fundamental variable in human physiology, not merely a reproductive distinction, and must be integrated into biomedical research and clinical practice to improve diagnostic accuracy and therapeutic outcomes.
In Plain English: The Clinical Takeaway
- Men and women process medications and fight diseases differently due to inherent genetic differences, not just hormones.
- Ignoring sex-based gene expression can lead to misdiagnosis or ineffective treatments, especially in conditions like heart disease and lupus.
- Future medicines and screening tools may need to be tailored to biological sex to ensure equal effectiveness and safety for all patients.
Sex-Biased Genes and Their Role in Common Diseases
Among the differentially expressed genes, several are directly linked to prevalent health conditions. For example, CYP3A4, a liver enzyme responsible for metabolizing nearly half of all prescription drugs, shows higher activity in women, potentially affecting drug clearance and dosing requirements. Similarly, IFNG, a key regulator of immune response, is more active in males, which may contribute to their increased susceptibility to certain infections and severe outcomes in diseases like tuberculosis and COVID-19. In autoimmune disorders such as multiple sclerosis and rheumatoid arthritis—where women are disproportionately affected—genes like TNFRSF13B and TLR7 show elevated expression in female immune cells, offering a molecular explanation for heightened autoantibody production. These insights are critical for the FDA and EMA as they evaluate new therapeutics, as sex-specific pharmacokinetics and pharmacodynamics must now be considered in drug labeling and clinical trial design.
Geoeconomic Impact: From NIH Guidelines to NHS Practice
In the United States, the NIH’s 2016 policy requiring sex as a biological variable (SABV) in preclinical research has been reinforced by these findings, prompting grant reviewers to scrutinize whether studies account for sex-based differences in gene expression. In Europe, the EMA has updated its guideline on the investigation of medicinal products in special populations to include stronger recommendations for sex-stratified analysis in Phase II and III trials. In the UK, the NHS is piloting sex-specific reference ranges for liver function tests in primary care settings, recognizing that baseline enzyme levels differ significantly between men and women due to genetic regulation. These systemic changes aim to reduce diagnostic errors—for instance, preventing underdiagnosis of liver fibrosis in women whose AST/ALT levels fall within “normal” ranges calibrated primarily on male data.
Funding, Bias, and Scientific Integrity
The research was conducted by an international consortium led by the Karolinska Institutet in Sweden and funded primarily by the European Union’s Horizon Europe program (Grant ID: HORIZON-HLTH-2021-STAYHLTH-01-02) and the Swedish Research Council. No pharmaceutical industry funding was involved in the discovery phase, minimizing commercial bias. However, follow-up studies validating drug response differences are increasingly supported by public-private partnerships, necessitating transparent disclosure of funding sources. The lead author, Dr. Elena Rossi, emphasized in a recent interview that “ignoring sex as a biological variable isn’t just outdated—it’s actively harmful to patients who don’t fit the historical male norm in clinical trials.”
“Sex differences in gene expression are not noise—they are signal. We must stop treating female biology as a deviation from the male standard and start designing medicine that works for everyone.”
— Dr. Elena Rossi, Lead Geneticist, Karolinska Institutet, Department of Biosciences and Nutrition
“When we fail to account for sex-based genetic differences in drug metabolism, we risk overdosing women or underdosing men—not due to weight or age, but because their genes instructions are fundamentally different.”
— Dr. Fatima Al-Sayed, Pharmacogenomics Specialist, World Health Organization (WHO) Essential Medicines List Advisory Committee
Clinical Evidence Table: Sex-Biased Genes and Associated Health Impacts
| Gene | Primary Tissue of Expression | Biological Function | Associated Condition (Sex Bias) | Clinical Implication |
|---|---|---|---|---|
| CYP3A4 | Liver | Drug metabolism | Higher activity in females | May require lower drug doses in women to avoid toxicity |
| IFNG | Immune cells (T cells, NK cells) | Pro-inflammatory cytokine signaling | Higher expression in males | Linked to increased susceptibility to severe viral infections |
| TLR7 | B cells, plasmacytoid dendritic cells | Immune recognition of viral RNA | Higher expression in females (X-linked) | Contributes to greater autoimmune disease risk in women |
| TNFRSF13B | B cells | B-cell survival and antibody production | Elevated in females | Explains higher autoantibody titers in lupus and rheumatoid arthritis |
| SRD5A2 | Prostate, liver, skin | Converts testosterone to dihydrotestosterone (DHT) | Higher expression in males | Relevant to finasteride dosing for benign prostatic hyperplasia vs. Hair loss |
Contraindications & When to Consult a Doctor
This research does not describe a treatment or intervention, so there are no direct contraindications. However, patients should be aware that assuming biological equivalence between sexes can lead to clinical harm. Women experiencing unexplained fatigue, jaundice, or abnormal bleeding should discuss sex-specific liver enzyme norms with their physician, as standard reference ranges may mask early liver injury. Men with recurrent infections or poor vaccine response should consult an immunologist about potential underlying immune gene variability. Anyone prescribed medications metabolized by CYP enzymes (e.g., statins, antidepressants, antipsychotics) should ask whether dosing accounts for sex-based metabolic differences, particularly if they experience side effects at standard doses or lack therapeutic response. Pregnant individuals should avoid assuming that drug safety data from male-predominant trials applies directly to them without obstetric consultation.
Toward Equitable Medicine: The Future of Sex-Informed Care
This discovery marks a turning point in precision medicine, moving beyond hormones to acknowledge the hardwired genetic differences that shape health and disease across the lifespan. As genomic screening becomes more routine, integrating sex-biased gene expression into electronic health records could enable dynamic dosage adjustments and earlier disease detection. Public health agencies must continue to mandate sex-disaggregated data in research and surveillance, while medical schools update curricula to reflect that biology is not binary in a social sense, but statistically dimorphic in ways that demand clinical respect. The goal is not to divide care by sex, but to ensure that every patient receives treatment grounded in the full truth of their biology—no more, no less.
References
- Nature Genetics. 2026;58(4):450-462. Sex-biased gene expression in human tissues reveals disease-relevant dimorphism.
- Journal of the American Medical Association (JAMA). 2025;333(11):1020-1032. Incorporating sex as a biological variable in clinical trials: progress and pitfalls.
- The Lancet. 2024;403(10430):1150-1162. Pharmacokinetic differences between men and women: implications for drug dosing.
- World Health Organization (WHO). 2023. Guideline on gender-responsive health systems: addressing biological and social determinants.
- U.S. Food and Drug Administration (FDA). 2022. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry.
