“I know this sounds like a cliché, but one of the main reasons I’m interested in learning about the genetic basis of heart disease is because my father’s side of the family has a terrible cardiovascular profile. If anyone understands the urgent need to identify novel targets for therapy, I certainly rank high on the list.” says Benjamin F. Voight, PhD, assistant professor of Pharmacology and Genetics at the Perelman School of Medicine, University of Pennsylvania. Voight’s father, a Major in the Air Force and a fighter pilot, passed away in his late 50s. He had his first heart attack in his late 30s, and as a result, suffered with vascular dementia, a decline in cognitive skills caused by blocked blood flow to the brain, depriving brain cells of oxygen and nutrients.“I’m motivated by asking, ‘What new biology can we uncover by direct studies in human patients?’” The interdisciplinary package of education and experience that he brings certainly speaks to that. As an undergrad, Voight double majored in math and biology at the University of Washington, Seattle, and then went to the University of Chicago for his Ph.D. in human genetics. He spent the next five years as a postdoc and a research scientist at the Broad Institute of Harvard and MIT in Boston.
In that same vein of questioning, this past spring, Voight published work he did while at the Broad, along with colleagues at the Massachusetts General Hospital and here at Penn, that challenges the conventional concept that raising a person's HDL levels – the good cholesterol -- will always lower their risk of a heart attack. In the study, published last May in The Lancet, the team analyzed previously identified DNA sequence variations directly associated with elevated HDL levels in humans. Looking at the genes of about 170,000 individuals, they discovered that none the established genetic variations actually reduced the risk of heart attack.
"The concept that genetic data can directly test the relationship between a biomarker like HDL to heart attack is an extremely potent one,” said Voight in a summary of the paper. All roads that raise HDL do not always lead to the promised land of reduced risk of heart attack, he adds. The paper’s findings question the viability of solely increasing good cholesterol levels to improve cardiovascular health.
"Clinicians and patients should continue to evaluate cholesterol levels to get a better picture of a patient's overall cardiovascular health, but we should carefully scrutinize intervention strategies based solely on increasing HDL to lower risk heart attack.”
Now at Penn for the last 18 months, Voight is asking a series of new questions related to heart disease: Are there common genetic factors that increase risk to heart disease if you have type-2 diabetes? This past fall he received an award from the W.W. Smith Charitable Trust to study the complex patterns of genetic inheritance and environmental factors that underlie cardiovascular disease specifically in type-2 diabetics.
“Despite the nearly two-fold increased rate of heart attacks in diabetic populations, we know next to nothing about the underlying biological causes for this elevated risk. My collaborators and I are on the hunt for elusive disease mechanisms and biological pathways contributing to this elevated risk. Closing this gap in knowledge is a key to clinical management of both diseases, as well as to identify biological targets for interventions." Voight says he will take advantage of his expertise and training in human statistical genetics, computational biology, and a great deal of collaborative effort across the globe, to advance this research.
Voight credits the improvement in genomic technology for his ability to ask these double-disease questions, which gives a better resolution of the kinds of variation researchers can identify about sequences of people with diabetes and heart disease: “We can get a better view of what is the same and different genetically in this population. That will be the first opportunity to understand what etiologically and potentially mechanistically has gone wrong in these patients.”
Voight notes that the road from genetics to therapies is a lengthy one, and thus it is critical to start with the best information possible. “We have a great opportunity to take what Mother Nature is telling us and understand what really matters. The hypotheses we will uncover, however, require a huge amount of work and collaborative efforts across many disciplines. My hope is that, with genetics, we can start from solid ground, identify the most promising targets, and take our best shots on goal to identify treatments.”