Loss of the Y chromosome in white blood cells can cause fibrosis in the heart
Impaired heart function, and death from cardiovascular disease (CVD) in men, according to the results of a study published in Science. Up until now, there has been no clear causal relationship identified.
However, previous study results have shown that men with mosaic loss of Y (mLOY) in their blood have an increased risk of developing an age-related disease, such as Alzheimer’s disease and cancer.
This study established a causal relationship when investigators from Uppsala University used the gene-editing tool, CRISPR, to generate mouse models with mLOY in their white blood cells.
They found that mLOY caused direct damage to the animals’ organs and that mice with mLOY had shorter survival 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,” Lars Forsberg, associate professor at the department of immunology, genetics, and pathology at Uppsala University, said in a statement. “Examination of mice with mLOY showed increased scarring of the heart, known as fibrosis. We see that mLOY causes fibrosis which leads to a decline in heart function,” Forsberg said.
Investigators also were able to corroborate the causal effect in mouse via epidemiological studies in humans. They found that mLOY was a new significant risk factor for death from CVD in men.
They found that men with mLOY in their blood at the start of the study displayed an approximately 30% increased risk of dying from heart failure and other types of CVD during the 11 years of 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,” Forsberg said.
These studies were performed using data from the United Kingdom Biobank, a database with genomic and health information from half a million normally ageing individuals aged 40 to 70 years at the start of the study.
The study described the mechanism by which mLOY in the blood causes disease in other organs and further identifies a possible treatment. Additionally, mLOY in a certain type of white blood cell in the heart of mice, called cardiac macrophages, stimulates a known signalling pathway that leads to increased fibrosis.
When the research blocked the pathway, the pathological changes in the heart could be reversed.
“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 particularly well to such treatment,” Forsberg said.