Keating and his colleagues also found that the Y1102 polymorphism occurred disproportionately in African-American patients with arrhythmia and in all phenotypically affected members of one African-American family.
"It would appear that this variant originated in Africa long ago, and been in that population for some time," said Keating. "And the people who migrated out of Africa to found other populations still carry it."
The scientists also conducted cell culture studies that revealed how the Y1102 variant affected the sodium channel by subtly altering its "gating," causing it to remain open slightly longer, which prolongs action potential duration and increases the excitability of cardiac muscle cells. This effect could cause transient conduction abnormalities between heart cells, contributing to arrhythmia risk. Finally, the scientists compared a computer simulation of the effects of Y1102 with actual clinical findings of drug effects on arrhythmia, discovering that the polymorphism did produce the predicted sensitivity.
While the researchers hope their findings will benefit people who have the Y1102 variant, they also emphasize the broader implications of their discovery. "We believe this finding is especially significant because it constitutes a proof of principle that points the way to identifying more of these variants in different population groups," said Keating.
"This is among the first pieces of a big puzzle of genetic affects on arrhythmia," he said. "We need to have many more pieces before we can begin large-scale genetic testing of people for such variants. And although testing for the variant we have discovered may prove useful, it is only one of many risk factors. So, I would hope that such testing will b
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
22-Aug-2002