Loss of Y chromosomal signatures in cardiovascular disease

The most common form of clonal somatic mosaicism in men is mosaic loss of the Y chromosome (mLOY) in leukocytes, where a subset of cells loses Y-chromosomal material. mLOY has been linked to increased mortality and impaired cardiovascular function.³ Interestingly, known modifiable cardiovascular risk factors contribute only about 50 % to the ten-year incidence of cardiovascular disease in men. This leaves an approximately 50 % gap in our understanding of risk factors that might explain cardiovascular disease.⁴ mLOY represents one such detectable risk factor for cardiovascular disease. 

The presented study investigated the association between mLOY and the blood proteome, as well as the resulting cardiovascular outcomes. Data were obtained from the UK Biobank. In total, single nucleotide polymorphism (SNP) array intensity data for 20,645 male individuals (mean age 57.1±8.3 years) were analyzed. Plasma proteomic profiles covering ~3,000 proteins were generated using the OLINK Explore 1536 platform. Associations between protein levels and mLOY burden were tested using linear regression models adjusted for age, smoking, BMI, hypertension, diabetes, LDL-C, and genetic ancestry. A Bonferroni-corrected p-value <0.05 was considered significant. Transcriptional changes related to mLOY were assessed using single-cell RNA sequencing (scRNA-seq) of circulating mononuclear blood cells.

A total of 332 proteins were significantly associated with mLOY, including 127 upregulated and 205 downregulated proteins. Among the top upregulated proteins was TCL1A, consistent with prior evidence of its role in genetic susceptibility. The validity of the method was further confirmed by the downregulation of CSF2RA and CD99, both located in the Y-chromosomal PAR1 region. STRING-db pathway enrichment analysis showed an overrepresentation of pathways related to inflammation, immune regulation, and extracellular matrix organization.

Eleven mLOY-upregulated proteins were significantly associated with incident cardiovascular diseases, including heart failure, atrial fibrillation, hypertensive heart disease, and aortic aneurysm. These eleven proteins could be clustered into four functional categories: profibrotic mediators, general inflammatory markers, monocyte-specific activation markers, and immune modulators or immune suppressive proteins. Increases in plasma levels of any of these proteins were linked to a higher risk of both all-cause and cardiovascular mortality.

Validation of the proteomic signatures was performed using scRNA-seq. Of the 173 proteins significantly associated with incident heart failure, 47 showed transcriptional profiles concordant with their plasma protein counterparts. Genes upregulated in peripheral blood mononuclear cells demonstrated pathway enrichment related to inflammation and the adaptive immune system, consistent with the plasma proteomic signature. Specifically, the upregulated genes in mLOY cells included those genes coding for the proteins PLAUR, CD300E, LILRA5, TNFRSF10B, and LAMP3, which all were significantly associated with the incidence for and mortality of all four cardiovascular disease conditions, heart failure, atrial fibrillation, hypertensive heart disease, and aortic aneurysm.

The study demonstrated that mLOY is strongly associated with plasma proteomic changes relevant to cardiovascular disease. mLOY should therefore not be viewed merely as an age-related somatic mutation but may serve as a novel risk factor for cardiovascular disease and potentially as a therapeutic target in men at risk of cardiovascular events.

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