New York (ISJ) ? A study by scientists at the Stanford University School of Medicine finds genetic mutation increases the risk of heart diseases. They have found this by comparing heart muscle cells made from induced pluripotent stem cells, or iPS cells created from skin samples in laboratory with that of people with mutation and without mutation. Pluripotent cell means, cells that 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."
"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," Prof. Wu added.
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 diseases and poorer outcome after a heart attack. Aldehyde dehydrogenase 2 also known as ALDH2, is a human gene found on chromosome 12.
The iPS cells in this study were created from skin samples donated by 10 men, ages 21-22, of East Asian descent.
The use of heart muscle cells derived from iPS cells has opened important doors for scientists because tissue samples can easily be 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.
About 8 percent of the world?s population carries the mutation in one of their two copies of the ALDH2 gene, which encodes a protein known as aldehyde dehydrogenase 2. The mutation in the gene short-circuits the production of the functional protein. (Because most carriers have one normal and one mutated copy of the gene, they are not completely lacking in the functional ALDH2 protein.)
One of ALDH2's many jobs in a cell is to seek out and neutralize toxic aldehydes, harmful substances caused by a class of compounds called reactive oxygen species. One toxic aldehyde, called 4HNE, causes the accumulation of yet more reactive oxygen species. Left to their own devices, high levels of reactive oxygen species can signal a cell to undergo programmed cell death in response to stress, such as the lack of oxygen that mimics what happens during a heart attack.
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.
Image: Stem-cell-derived heart muscle cells (green) with a mutation in the ALDH2 gene after oxygen deprivation mimicking a heart attack. The red spots indicate fragmented DNA (a marker of cell death) while the blue areas are the nuclei of the cells.
Source: Stanford University
Image courtesy: Joseph Wu