Sex-specific proteomic risk scores reveal distinct cardiovascular risk profiles and improve prediction of major adverse cardiovascular events in hypertension

Abstract Background Individuals with hypertension face a substantial residual risk of major adverse cardiovascular events (MACE), yet current clinical risk models often fail to capture the complex pathophysiological heterogeneity and sex differences within this population. This study leveraged large-scale proteomic data to develop sex-stratified protein risk scores for improving 10-year MACE prediction in individuals with hypertension. Methods We included 27,510 hypertensive participants from the UK Biobank Pharma Proteomics Project (UKB-PPP) who underwent baseline plasma proteomic profiling. In the training cohort, we employed a sex-stratified Least Absolute Shrinkage and Selection Operator (LASSO) strategy to select proteins for inclusion in male- and female-derived protein risk scores, and additionally constructed a simplified score comprising the top 10 weighted proteins for each sex. In the validation set, we estimated the association between these scores and MACE and verified their incremental predictive value over the SCORE2 model. Results A total of 28 and 23 priority proteins were identified for men and women, respectively, with five proteins (MMP12, NT-proBNP, NEFL, BCAN, and ADAMTS13) shared across both sexes. In the simplified scores, only two proteins overlapped between the sexes. Participants in the highest protein risk group had a significantly higher risk of MACE compared to those in the lowest risk group (Adjusted HR: Male: 2.68 [95% CI 1.97–3.64]; Female: 3.12 [95% CI 2.20–4.43]). Integrating these scores significantly improved the C-statistic (Male: 0.667 vs. 0.627; Female: 0.695 vs. 0.657) and category-based Net Reclassification Improvement (NRI: Male: 22.4% [95% CI 14.8%–30.2%]; Female: 14.0% [95% CI 5.8%–22.4%]) over SCORE2. Simplified protein scores maintained predictive performance comparable to the full models, indicating that much of the predictive information could be retained using a smaller protein panel. Conclusion Protein biomarkers may more accurately capture residual cardiovascular risk in hypertension. The sex-stratified protein risk scores may capture differently weighted proteomic correlates of cardiovascular risk in men and women, providing preliminary evidence for further evaluation of proteomic risk stratification in hypertension. However, external validation in independent and more diverse cohorts is required to establish the transportability and clinical utility of these scores.