Now chief of human genetics at the University of Texas Southwestern Medical Center at Dallas, her desire for better treatments drives her to pore over susceptibility factors to learn who develops disease and who does not—and why.
HHMI: WHAT AFFECTS A PERSON'S DISEASE SUSCEPTIBILITY?
HHH: The expression of a person's genes over time, in the context of environmental factors such as exercise, diet, aging, and stress, produces susceptibility or resistance to certain diseases. The term phenotype is used to capture the physical and biochemical characteristics that result from this interplay of genes and the environment. Phenotype in humans includes not only overt effects, like a heart attack or stroke, but the more subtle changes we uncover through blood tests and imaging studies.
HHMI: HOW ARE YOU USING PHENOTYPE ANALYSIS IN YOUR RESEARCH?
HHH: We've used sophisticated imaging together with more conventional medical testing to develop very precise phenotypes in a large study population. In the Dallas Heart Study, we enrolled 3,500 individuals—African American, Hispanic, and Caucasian—between 30 and 65 years of age, and obtained a series of phenotypes for each participant, including imaging studies to visualize the heart, blood vessels, liver, and other tissues and blood tests to measure the levels of many different proteins and lipids.
HHMI: WHAT HAVE YOU FOUND?
HHH: Our work with a gene called PCSK9 is the most significant contribution of the Dallas Heart Study. We discovered that variant forms of PCSK9 are associated with lower levels of low-density lipoproteins (LDL), the “bad” cholesterol. We found that one out of every 50 African Americans has a PCSK9 variant associated with a 28 percent reduction in LDL; Caucasians with a different variant experience a 15 percent reduction in LDL.
We assessed these PCSK9 variations in more than 12,000 samples collected in the Atherosclerosis Risk in Communities Study across 15 years. The findings were unequivocal: low LDL is remarkably cardioprotective. The African Americans with the PCSK9 mutations had an 88 percent decrease in heart disease risk—and this included many individuals with hypertension or diabetes, or those who smoked. The Caucasians with the other PCSK9 sequence variation had a 50 percent disease risk reduction. These are much greater reductions in coronary heart disease than we see when we lower plasma LDL to similar levels with a statin drug in adults.
We published those results in 2006. It now seems reasonable to consider lowering LDL during early adulthood in individuals who have other risk factors. The NIH is considering a trial to test this, and pharmaceutical companies are looking at PCSK9 as a drug target.
Photo: Brian Harkin
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