Higher cardiovascular disease mortality with loss of Y chromosome
Older men without Y-chromosomes in their white blood cells have an increased risk of heart disease and death, according to a study co-led by SciLifeLab researcher Lars Forsberg at Uppsala University. The SciLifeLab National Bioinformatics Infrastructure Sweden (NBIS) facilitated the analyses of biobank data at UPPMAX.
Mosaic Loss Of Y (mLOY), is a genetic change where men lose the Y chromosome in their white blood cells. The loss is quite common and has been detected in every fifth 60-year-old and in two out of five men in their 70s.
Previous studies have ascertained a connection between mLOY, cancer, and Alzheimer’s disease. But there are also links between chromosome loss and the on average lower lifespan of males.
A research group from Uppsala University, co-lead by the corresponding author and SciLifeLab researcher Lars Forsberg (Uppsala University), decided to take a closer look at the effects of mLOY on the disease progression in different organs. In a groundbreaking study published in Science, they managed to establish a link between mLOY presence in white blood cells and an increased risk of death from cardiovascular disease.
Using CRISPR for gene editing, the researchers reared mice with mLOY in their white blood cells. This group of mice experienced direct damage to their internal organs, and died earlier than mice without mLOY.
“In the mouse models used in the study, the mouse Y chromosome was eliminated to mimic the human mLOY condition, and we analyzed the direct consequences that this had. Examination of mice with mLOY showed increased scarring of the heart, known as so-called fibrosis. We see that mLOY causes the fibrosis, which leads to a decline in heart function,” says Lars Forsberg in a press release from Uppsala University.
Using a UK Biobank database with genomic health information from 500 000 normally aged individuals between 40 and 70 years, the researchers could compare their mouse data with epidemiological studies in humans.
When men had mLOY present in their blood already at the start of the UK study, the risk of dying from cardiovascular diseases such as heart failure was approximately 30 percent higher during the 11-year follow-up.
“We also see that men with a higher proportion of white blood cells with mLOY in the blood have a greater risk of dying from cardiovascular disease. This observation is in line with the results from the mouse model and suggests that mLOY has a direct physiological effect also in humans,” says Lars Forsberg.
“The link between mLOY and fibrosis is very interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis, and certain cancers that aim to counteract the onset of fibrosis. Men with mLOY could be a patient group that responds extra particularly well to such treatment,” he adds.
Large datasets usually need to be analyzed on high-performance computing systems. Swedish academic researchers can apply for compute and storage allocations at systems provided by The Swedish National Infrastructure for Computing (SNIC), such as the UPPMAX systems.
“We used UPPMAX infrastructure for analyzes of UK Biobank data”, says Lars Forsberg.
The SciLifeLab National Bioinformatics Infrastructure Sweden (NBIS) maintains bioinformatics software and data on UPPMAX and offers associated user support.
