Mosaic loss of the Y chromosome (mLOY) is the most common acquired mutation in ageing men and has been linked to higher cardiovascular risk, but its systemic molecular footprint has remained unclear.
Weyrich and colleagues profiled the plasma proteome of 20,645 men from the UK Biobank using the Olink Explore 1536 panel and uncovered 332 proteins whose levels track with mLOY burden. These signals prominently map to inflammation, immune regulation, extracellular-matrix organisation and fibrosis—pointing to immune–fibrotic pathways as a hallmark of mLOY.
Strikingly, many of these proteins predicted incident cardiovascular disease: heart failure showed the largest overlap, followed by atrial fibrillation, aortic aneurysm and hypertensive heart disease. Eleven mLOY-upregulated proteins - including WFDC2, GDF15, PLAUR, CXCL17, CD300E, LILRA5, LAMP3, TNFRSF10B, MSLN, TFF2 and CEACAM5 - were associated across all four conditions and each related to increased all-cause and cardiovascular mortality.
Single-cell RNA-seq of blood mononuclear cells from heart-failure patients further mirrored these plasma changes, revealing concordant upregulation of genes encoding several of the same proteins in cells lacking Y-chromosome expression. Together, the work provides the first comprehensive plasma proteomic signature of mLOY, links it to adverse cardiovascular outcomes, and highlights targetable biomarkers and pathways that may open new avenues for risk stratification and therapy in men with mLOY.

Find the full article here: Loss of Y chromosome: proteomic signatures in human cardiovascular disease | European Heart Journal | Oxford Academic