Loss of the Y chromosome in men and risk of heart disease

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About 20% of men have lost their Y chromosome by the age of 60. Maskot/Getty Images
  • By age 70, about 40% of men have lost their Y chromosome.
  • Researchers say this loss, sometimes known as mLOY, may increase the risk of heart disease in older men.
  • Experts say there are tests that can be done to determine if a man has lost his Y chromosome and preventive measures can be taken to reduce the risk of heart disease.

It may come as a surprise that many older men lose the Y chromosome from their white blood cells when they reach a certain age.

Now, new research reveals that this genetic change can cause serious heart problems and increase the risk of death from cardiovascular disease.

Known as mLOY, or Mosaic Loss of Ythis genetic change affects at least 20% of 60-year-old men and 40% of 70-year-old men, according to researchers from the University of Virginia and Uppsala University in Sweden.

“Y is lost during cell division and is more common in tissues and organs with high cell division rates, such as blood,” said study co-author and professor Lars Forsberg, Ph.D. associate in the Department of Immunology. , Genetics and Pathology at Uppsala University, Healthline told Healthline. “The replicated risk factors are age, smoking and genetic predisposition.”

The new study, led by Forsberg and Kenneth Walsh, Ph.D., professor of cardiovascular medicine at the University of Virginia School of Medicine, establishes a causal link between chromosome loss and the development of fibrosis in the heart, impaired heart function, and death from cardiovascular disease in men.

The researchers used the gene-editing tool CRISPR to remove the Y chromosome from white blood cells in lab mice. They found that mLOY caused direct damage to the animals’ internal organs and that mice with mLOY died younger than mice without mLOY.

“Examination of mice with mLOY showed increased scarring of the heart, known as fibrosis. We see that mLOY causes the fibrosis which leads to a decline in heart function,” Forsberg said.

The researchers reported that mLOY in a certain type of white blood cells in heart muscle, called cardiac macrophages, stimulated a known signaling pathway that leads to increased fibrosis.

When the researchers blocked this pathway, known as high transforming growth factor β1 (TGF-β1), they said the pathological changes in the heart caused by mLOY could be reversed.

An epidemiological study in humans has also shown that mLOY is an important risk factor for death from cardiovascular disease in humans.

For this part of the study, Forsberg, Walsh and their colleagues looked at genetic and cardiovascular data from 500,000 people aged 40 to 70 in the UK Biobank.

Researchers reported that people with mLOY at the start of the study had an approximately 30% higher risk of dying from heart disease over the 11-year follow-up period than those who did not have mLOY. .

“This observation is consistent with results from the mouse model and suggests that mLOY has a direct physiological effect in humans as well,” Forsberg said.

The type of heart disease associated with mLOY is called non-ischemic heart failure.

“This form is poorly understood compared to classic ischemic heart failure, [which] results from the blockage of a major artery that supplies blood to the heart muscle,” Forsberg said.

He added that there are “very few treatment options” available for non-ischemic heart failure.

“We could think of it as identifying what we might otherwise call age-related degeneration,” Dr. Rigved Tadwalkar, a cardiologist at Providence Saint John’s Health Center in California, told Healthline. “It gives us a goal to try to mitigate these effects of aging.”

Forsberg said routine testing for Y chromosome loss in blood cells could help prevent cardiovascular disease.

“mLOY tests on aging men could identify… men [who] would likely benefit from medical checkups and preventative treatment,” Forsberg said. “Loss of the Y chromosome can be relatively easy to measure. If validated by further research, the loss of Y can be used as a prognostic test or it can potentially be used to guide therapies.

“For example, men with mLOY in their blood might be asked to have an MRI (magnetic resonance imaging) scan to determine if he has connective tissue buildup/fibrosis in his heart and other organs,” a- he declared. “If that turns out to be the case, he could be put on anti-fibrotic drugs.”

“An FDA-approved antifibrotic drug exists for idiopathic pulmonary fibrosis and this drug is currently being explored for its usefulness in conditions involving cardiac and renal fibrosis,” Forsberg added. “In addition, pharmaceutical companies are very interested in the development of new drugs against fibrosis. It is possible that men who have lost the Y chromosome have a better response to these drugs.

Previous studies have also suggested that mLOY is linked to excessive fibrosis in the kidneys and lungs. Researchers have also begun to lay the groundwork for the creation of a genetic screening test to assess the risk of mLOY.

Tadwalkar said mLOY is “certainly not brought up in day-to-day clinical practice” among cardiologists.

Although therapies to treat mLOY are currently limited, he said, a cost-effective screening test would at least help put the condition on clinicians’ radar.

It could also provide an opportunity to assess patients for other cardiovascular risk factors that can be treated.

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