The Newton-Cheh Laboratory seeks
to identify the genetic contributions to
common cardiovascular diseases including
sudden cardiac death, drug-induced QT prolongation,
and hypertension. The explosion in genetic
information available from the Human Genome
Project and the International HapMap project
coupled with the developments of high-throughput
genotyping methods and analytical and statistical
approaches needed to analyze large, multidimensional
datasets enable the efficient testing of
the majority of human genetic variation
for its contribution to human disease. We
are currently studying the genetics of quantitative
risk factors, including electrocardiographic
QT interval duration and blood pressure,
in large collections of human population-based
samples and testing validated risk alleles
for association with cardiovascular outcomes
such as sudden cardiac death.
Sudden Cardiac Death
Sudden cardiac death (SCD) is a common cardiovascular
disease that claims 300,000 lives annually
in the US and has been shown to be influenced
by genetic factors. To date, the search
for causal genes for common diseases such
as sudden death has been difficult. It is
now possible, for the first time, to search
comprehensively for genetic variants that
influence susceptibility to cardiovascular
diseases through genome-wide association
studies (GWAS). Because most common genetic
variants have modest effects, detecting
these at appropriately rigorous statistical
thresholds requires large sample sizes.
In the case of sudden death, it has been
difficult to collect large, well-controlled
sudden death cohorts and the small cohorts
currently available are insufficiently powered
to withstand the correction for multiple
hypothesis testing inherent in GWAS.
Fortunately, there are intermediate and
heritable traits such as electrocardiographic
QT interval (QT) that contribute to the
risk of SCD and are more tractable for research
because they are available in large samples.
QT prolongation, reflecting delayed myocardial
repolarization, has been a consistent risk
factor for SCD in most community-based studies.
Moreover, beyond its contribution to SCD
risk, the QT interval is an important quantitative
cardiovascular phenotype because QT prolongation
in response to medications leading to sudden
death has led to the withdrawal of many
otherwise effective non-cardiac medications,
at great health and financial cost to society.
We are conducting large-scale multistage
GWAS of QT interval duration to identify
novel genetic variants that reproducibly
influence QT interval duration and then
testing alleles influencing QT interval
for their effects on risk of sudden cardiac
death. In addition, we are resequencing
these novel genes to characterize the full
spectrum of genetic variation at each locus
that contributes to variation in QT interval
duration.
Blood pressure
Increasing blood pressure elevation has
a continuous and graded contribution to
the population burden of myocardial infarction,
stroke, heart failure and chronic kidney
disease. Elevated blood pressure (hypertension)
affects an estimated 1 billion people world-wide.
Blood pressure (BP) is a complex trait with
multiple environmental and genetic influences.
Blood pressure is highly heritable, but
to date the genetic causes of variation
in blood pressure in the general population
have been poorly defined. Individually rare
gain or loss of function mutations in several
genes involved in renal salt handling cause
sodium retention or wasting with resultant
Mendelian forms of hypertension or hypotension
and early onset of disease. Recently, rare
variation in these genes has also been found
to contribute to lower blood pressure in
the general population. To date, no common
variants have been reproducibly related
to blood pressure variation in the general
population. We are pursuing the genetic
underpinnings of blood pressure in the general
population using large-scale genome-wide
association study of blood pressure and
intermediate traits such as blood biomarkers.
Collaborations
To define the role of genetic variation
in the general population requires the study
of tens of thousands of samples of well-phenotyped
individuals with available DNA. We have
developed close collaborations with investigators
across the US and in Finland, Germany, the
Netherlands, Sweden, and the United Kingdom.
We participate actively in several large
consortia tackling the genetic basis of
QT interval variation, sudden death, and
hypertension.
Background
Dr. Newton-Cheh earned a BA from Dartmouth
College in 1991. He attended medical school
at Columbia University College of Physicians
and Surgeons from 1992 to 1996. He trained
in internal medicine and cardiology from
1996 to 2001 at the Massachusetts General
Hospital, where he subsequently served as
medical chief resident from 2001-2002. He
completed a postdoctoral fellowship in complex
trait genetics at the Broad Institute of
Harvard and MIT (originally the Whitehead
Institute Center for Genetic Research) with
Joel N. Hirschhorn, MD, PhD and in cardiovascular
epidemiology at the Framingham Heart Study
with Christopher J. O’Donnell, MD,
MPH from 2002 to 2007. He obtained a Master
of Public Health from the Harvard School
of Public Health in 2004.
Dr. Newton-Cheh is on the faculty of the
Center for Human Genetic Research and the
Cardiovascular Research Center, where he
co-directs the Human Cardiovascular Genetics
Program, both of Massachusetts General Hospital
and Harvard Medical School. Dr. Newton-Cheh
is a staff physician in the Heart Failure
and Cardiac Transplantation Center at the
Massachusetts General Hospital. Dr. Newton-Cheh
receives support from the NIH, the Doris
Duke Charitable Foundation and the Burroughs
Wellcome Fund.
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