Genomics research: New genetic 'hit list' may underlie susceptibility to sudden cardiac death

December 30, 2003

ROCHESTER, Minn. -- Researchers at Mayo Clinic have discovered that genetic variants associated with instances of sudden cardiac deaths are far more prevalent and diverse than first thought -- especially among minorities. The news comes from a study on a specific cardiac disorder affecting young people -- long QT syndrome -- which may kill as many as 3,000 teenagers and young adults in the United States annually.

"These findings are critical for the proper interpretation of genetic tests for diagnosing long QT syndrome," says principal author Michael Ackerman, M.D., Ph.D. "This extensive data set will aid in that interpretation and help investigators explore whether any of these new variants increase susceptibility to sudden cardiac death, which claims 350,000 lives each year."

The findings are published in the December issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2003;78:1479-1487).

Long QT syndrome results from a primary genetic glitch involving the heart's electrical system and can cause episodes of fainting, seizing or sudden death. Its presence can often be detected with an electrocardiogram (ECG) where the interval between points Q and T is abnormally prolonged. If untreated, half the people with symptomatic long QT syndrome will die within ten years after the first symptoms are noticed.

First Genomics Analysis of Healthy Population

Mayo researchers conducted a comprehensive DNA analysis of 744 healthy volunteers from among four ethnic groups. This study group was unusual, not only for its size compared to previous studies, but because it included sufficient numbers of minorities to make findings statistically significant for those subgroups. The study included 305 black, 187 white, 134 Asian and 118 Hispanic individuals. Previous studies examined groups that included only long QT patients and their families, looking for genetic variants that cause this inherited syndrome. This Mayo-led study is the first comprehensive analysis of a large group of healthy persons for gene mutations that could increase susceptibility to sudden cardiac death.

Surprising Prevalence of Variants

Inherited long QT syndrome occurs when a defect develops in one or more of the genes that program the ion channels of the heart. The ion channels are "electrical tunnels" that produce and control the heart's electrical activity. A key finding of this study: far more potassium channel variants exist than were anticipated. The study identified 49 distinct variants among the healthy population examined -- 36 of the variants or 73 percent were previously unknown. Eighty-six percent of the variants were found only in specific ethnic groups. When researchers excluded the most common and established potassium channel variants, one in three blacks and one in seven whites studied were found to harbor at least one variant. Based on previous studies, a potassium channel mutation causing inherited long QT syndrome should be expected in only one out of every 10,000 individuals.

Impacts Future Diagnosis for Blacks

The researchers say the findings have a profound impact on diagnosis and future testing for long QT syndrome. Because of the large number of variants found in such a diverse, healthy group of individuals, researchers say physicians need to use extreme care in diagnosing newly-discovered variants as disease-causing mutations -- especially among minority patients.

"This new compendium of channel variants is a 'hit list' of suspects for investigators aiming at the larger issue of sudden cardiac death," says Dr. Ackerman. "We don't know if any of these variants cause increased susceptibility to external causes, such as medications, but the new data provides an exciting opportunity for important studies."

For example, one variant -- Q9E-MiRP1 -- previously identified as a disease-causing arrhythmia mutation -- had not been seen in over one thousand control subjects. Yet this study showed that Q9E-MiRP1 is present in about five percent of blacks and therefore could predispose thousands of minority individuals to drug-induced sudden death.

Previous study methods would have inappropriately labeled nearly all 36 newly-identified variants as disease-causing mutations. More research must be done to determine if the higher frequency of channel variants indicates an increased risk for fatal arrhythmias.

Co-authors of the article include David Tester and Melissa Will, Mayo Clinic, and Christopher Burrow, M.D., Mark Curran, Ph.D., and Gregg Jones, formerly of DNA Sciences, Inc., Fremont, Calif.

Mayo Clinic conducts research in medical genomics and proteomics in order to improve patient care. Its scientists and clinical investigators strive to turn laboratory discoveries into beneficial therapies as quickly as possible. Patient privacy and confidentiality in research studies are ensured.

Mayo Clinic

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