Harvard Catalyst Profiles

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.