Over 500 million people worldwide carry the genetic mutation that disables a common metabolic protein called ALDH2. The mutation also causes facial flushing when carriers drink alcohol.

Researchers at the Stanford University School of Medicine have learned for the first time specifically how the mutation affects heart health. They did so by comparing heart muscle cells made from induced pluripotent stem cells, or iPS cells, from people with the mutation versus those without the mutation.

 The iPS cells are created in the laboratory from specialised adult cells like skin. They are "pluripotent," meaning they can be coaxed to become any cell in the body.

"This study is one of the first to show that we can use iPS cells to study ethnic-specific differences among populations," said Joseph Wu, director of the Stanford Cardiovascular Institute and professor of cardiovascular medicine and of radiology.

"These findings may help us discover new therapeutic paths for heart disease for carriers of this mutation," said Wu.

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It's the first time ALDH2 has been shown to play a role in cell survival.

ALDH2 activity, or the lack of it, influences whether a cell enters a state of programmed cell death called apoptosis in response to stressful growing conditions. The iPS cells in the study were created from skin samples donated by 10 men, ages 21-22, of East Asian descent.

Researchers first studied the skin cells obtained from the volunteers. Five of the 10 volunteers had an ALDH2 mutation; the other five did not. The researchers found that skin cells with the mutation in the ALDH2 gene had strongly decreased function of the ALDH2 protein compared with the cells without the mutation.

The mutated cells also had significantly higher amounts of reactive oxygen species, and grew more slowly than the other cells.

They next created iPS cells from the donated skinsamples, and stimulated the iPS cells to become heart muscle cells called cardiomyocytes. They then compared how the newly created cardiomyocytes responded to low-oxygen conditions.

Cardiomyocytes with the ALDH2 mutation had higher levels of reactive oxygen species in response to low oxygen levels than those without the mutation, but this difference could be alleviated by treating the cells with a compound that boosts activity of the ALDH2 protein in patients with one unmutated copy of the gene.

Cells with the mutation also were less viable and more likely to undergo programmed cell death than were cells without the mutation.


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