“Our previous research has shown that deletions of the entire Y chromosome contribute to heart disease in men,” said Walsh, director of UVA’s Center for Blood and Vascular Biology. “This new study identifies a single gene on the Y chromosome that may be responsible for the disease-promoting effects of Y chromosome loss.”

About loss of Y chromosome

Unlike women, who have two X chromosomes, men have an X and a Y. For a long time, genes located on the Y chromosome were not thought to play an important role in disease. Scientists thought that sex hormones explain the differences in certain diseases between men and women.

But Walsh’s groundbreaking research helped change that perception. The study also suggested an explanation for why heart failure is more common in men than women. Cardiovascular diseases, including heart failure, are the leading cause of death worldwide.

Loss of the Y chromosome occurs in only a small percentage of an affected male’s cells. As a result, a so-called “mosaic phenomenon” occurs in which genetically different cells occur within a single individual. Researchers do not fully understand why this partial loss of the Y chromosome occurs, but it occurs primarily in older men and in men who smoke compared to men who do not smoke.

To better understand the effects of Y chromosome loss, Walsh and his team examined the genes found on the Y chromosome to determine which are important for heart scarring. One of the genes the researchers looked at, Uty, the scientists found, helps control instructions for immune cells called macrophages and monocytes.

When the genes were disrupted individually or by loss of the Y chromosome, it caused changes in the immune cells of laboratory mice. Suddenly, the macrophages became much more “pro-fibrotic,” or prone to scarring. Scientists have discovered that this also promotes heart failure.

Researcher Kenneth Walsh said the discovery was made based on his team’s previous work that identified loss of the entire Y chromosome as contributing to heart disease in men. (Photo courtesy of Dan Addison, University Communications)

“Identification of a single gene on the Y chromosome provides information on new druggable targets for treating fibrotic diseases,” said UVA’s Department of Cardiovascular Medicine and Robert M. Byrne Center for Cardiovascular Research. said Professor Walsh, who is also affiliated with the Institute.

By giving mice specially designed monoclonal antibodies, Walsh and his team were able to prevent harmful changes in macrophages. This stopped harmful changes in the heart, suggesting that, with further research, this approach could lead to a way to treat or avoid heart failure and other fibrotic diseases in men lacking the Y chromosome.

“We are currently working with clinical colleagues in UVA’s cardiology department to assess whether loss of the Y chromosome in men is associated with greater scarring of the heart,” said Professor Walsh. Ta. “This study will provide a new avenue for understanding the causes of heart disease.”

Based on this discovery, Walsh and his team believe that a small group of genes found on the Y chromosome may have a major impact on a wide range of diseases. Their new study identifies a mechanism that may lead to this, and they hope that further research will provide a better understanding of the unknown causes of illness and death in men.

“This study provides further evidence of the usefulness of studying the genetics of mutations that are acquired after conception and accumulate throughout life,” Professor Walsh said. “These mutations appear to be as important for health and longevity as mutations inherited from our parents. The study of these age-related mutations represents a new field in human genetics.”

Publication of survey results

The researchers published their findings in the scientific journal Nature Cardiovascular Research. The team includes Keita Horitani, Nicholas W. Chavkin, Yohei Arai, Wang Ying, Hayato Ogawa, Mitsu Yura, Megan A. Evans, Jesse Cochran, Mark C. Tell, Ariel H. Polizio, Miho Sano, and Miura. Emily Yura, Yuka Arai, Heather Dobiak, Arthur P. Arnold, Bradley D. Gelfand, Karen K. Hershi, Soichi Sano, Walsh. The scientists have no financial interest in this research.