Over 500 million people worldwide carry a genetic mutation that disables a common metabolic protein called ALDH2. The mutation, which predominantly occurs in people of East Asian descent, leads to an increased risk of heart disease and poorer outcomes after a heart attack. It also causes facial flushing when carriers drink alcohol.

Now 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. IPS cells are created in the laboratory from specialized 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, MD, PhD, 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. "In the future, I believe we will have banks of iPS cells generated from many different ethnic groups. Drug companies or clinicians can then compare how members of different ethnic groups respond to drugs or diseases, or study how one group might differ from another, or tailor specific drugs to fit particular groups."

The findings are described in a paper that will be published Sept. 24 in Science Translational Medicine. Wu and Daria Mochly-Rosen, PhD, professor of chemical and systems biology, are co-senior authors of the paper, and postdoctoral scholar Antje Ebert, PhD, is the lead author.

ALDH2 and cell death

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It is the first time ALDH2, which is involved in many common metabolic processes in cells of all types, has been shown to play a role in cell survival. In particular, 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 use of heart muscle cells derived from iPS cells has opened important doors for scientists because tissue samples can be easily obtained and maintained in the laboratory for study. Until recently, researchers had to confine their studies to genetically engineered mice or to human heart cells obtained through a heart biopsy, an invasive procedure that yields cells which are difficult to keep alive long term in the laboratory.

"People have studied the enzyme ALDH2 for many years in animal models," said Ebert. "But there are many significant differences between mice and humans. Now we can study actual human heart muscle cells, conveniently grown in the lab."

The iPS cells in this study were created from skin samples donated by 10 men, ages 21-22, of East Asian descent.

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Stem cells used to learn how common mutation in Asians affects heart health