Using a new genomic strategy that has the power to
survey the entire human genome and identify genes with
common variants that contribute to complex diseases,
researchers at Johns Hopkins, together with scientists from
Munich, Germany, and the Framingham Heart Study in the
United States have identified a gene that may predispose
some people to abnormal heart rhythms that lead to sudden
cardiac death, a condition affecting more than 300,000
Americans each year.
The gene called NOS1AP, not previously flagged by or
suspected from more traditional gene-hunting approaches,
appears to influence significantly one particular risk
factor — the so-called QT interval length — for
sudden cardiac death. The work was published online in
Nature Genetics on April 30.
"In addition to finding a genetic variant that could
be of clinical value for sudden cardiac death, this study
demonstrates how valuable large-scale genomics studies can
be in detecting novel biological targets," said the study's
senior author, Aravinda Chakravarti, director of the
McKusick-Nathans Institute for Genetic Medicine at
Johns Hopkins.
QT interval measures the period of time it takes the
heart to recover from the ventricular beat, when the two
bottom chambers of the heart pump. Corresponding to the
"lub" part of the "lub-dub" pattern of the heartbeat, an
individual's QT interval remains constant.
"There's a great deal of evidence out there that
having a too long or too short QT interval is a risk factor
for sudden cardiac death," said the study's co-first
author, Dan Arking, an instructor in the McKusick-Nathans
Institute. "This makes it appealing to study because it can
be measured noninvasively with an EKG, and each person's QT
interval, in the absence of a major cardiovascular event,
is stable over time, making it a reliable measure."
Identifying those at high risk for sudden cardiac
death before fatalities occur has been challenging at both
the clinical and genetic levels, said the study's other
first author, Arne Pfeufer, of the Institute of Human
Genetics at the Technical University in Munich. Doctors
estimate that in more than one-third of all cases, sudden
cardiac death is the first indication of heart disease. It
is widely believed that many factors, genetic and
environmental, contribute to irregular heartbeat and other
conditions that may lead to sudden cardiac death. Being
able to identify predisposed individuals can save their
lives by prescribing beta-blockers and other drugs that
regulate heart rhythm, and even by implanting automatic
defibrillators in those with the highest risk.
In an effort to identify risk factors with a genetic
foundation, the researchers took the unconventional
approach of starting from scratch and not looking at genes
already known or suspected to be involved in heart
rhythm.
"Studying individual genes is not going to open new
areas of research," Chakravarti said. "Using a whole-genome
approach allows us to find new targets that we never would
have imagined."
Instead of focusing on so-called candidate genes with
known functions that are highly suspect in heart beat
rhythm, the team first focused on people who have extremely
long or short QT intervals. The researchers used subjects
from two population-based studies, about 1,800 American
adults of European ancestry from the Framingham (Mass.)
Heart Study and about 6,700 German adults from the KORA-gen
study of Augsburg, Germany.
The research team then searched for any specific DNA
sequences that showed up more frequently in people who have
longer or shorter QT intervals than in those with normal QT
intervals. To do this, they examined the DNA sequences of
both long- and short-QT people. The human genome contains 3
billion letters, known as nucleotides. Each person's genome
differs from the next person's by as many as 10 million
nucleotides. The researchers looked for single nucleotide
variations — known as single nucleotide
polymorphisms, or SNPs for short — that track with
having a long or short QT interval.
Only one particular SNP correlated with QT interval.
That SNP was found near the NOS1AP gene, which has been
studied for its function in nerve cells and was not
previously suspected to play a role in heart function.
However, the research team found that the NOS1AP gene is
turned on in the left ventricle of the human heart. And the
"lub" part of the "lub-dub" heartbeat corresponds to
ventricular contraction. So NOS1AP is active in the right
place and time to play a role in QT interval.
Further studies revealed that approximately 60 percent
of people of European descent may carry at least one copy
of this SNP in the NOS1AP gene. According to the
researchers, this particular SNP is responsible for up to
1.5 percent of the difference in QT interval, meaning that
other genes, missed in this study, certainly contribute to
QT length.
Now that researchers know that variants of the NOS1AP
gene correlate with QT interval length, they hope to figure
out exactly how the DNA sequence variations alter the
function of the gene, and how changes in gene function
affect heart rhythm.
The Johns Hopkins researchers were funded chiefly by
the D.W. Reynolds Clinical Cardiovascular Research Center,
which focuses on sudden cardiac death. Additional support
was provided by The Johns Hopkins University, the National
Institutes of Health, a Glaxo-SmithKline Competitive Grants
Award Program for Young Investigators, an unrestricted
grant from Pfizer, and the German Federal Ministry of
Education and Research in the context of the German
National Genome Research Network. The Framingham Heart
Study is supported by the National Heart, Lung and Blood
Institute/Boston University School of Medicine and the
CardioGenomics Program for Genomic Applications.
Johns Hopkins authors on the paper are Arking, Wendy
Post, Linda Kao, Morna Ikeda, Kristen West, Carl Kashuk,
Eduardo Marban, Peter Spooner and Chakravarti.