Four-year, NIH-funded project continues Dr. Shuldiner's work with Pa. Amish community
Alan R. Shuldiner, M.D., the head of the Division of Endocrinology, Diabetes and Nutrition at the University of Maryland School of Medicine, has received a four-year, $10.6 million grant from the National Institutes of Health to study how genes and lifestyle factors influence people's risk of developing cardiovascular disease.
The study, funded by the NIH's National Heart, Lung and Blood Institute, will focus on 1,000 members of the Old Order Amish community in Lancaster County, Pa., who have already undergone extensive genetic testing as part of another study. Dr. Shuldiner and his team will measure how participants respond to four interventions that mimic lifestyle factors known to affect cardiovascular disease a high-fat meal, a high- and low-salt diet, aspirin and a cold stress stimulus and then look for genes that may explain differences in their cardiovascular responses.
This is really the first attempt to directly try to identify specific chromosomal regions and ultimately genes that interact with lifestyle characteristics to increase the risks of cardiovascular disease, says Dr. Shuldiner, a professor of medicine at the University of Maryland School of Medicine and the director of the University of Maryland Joslin Diabetes Center. We may be able to identify genes that can be used as markers to identify individuals at risk for cardiovascular disease or find new biological pathways, which could lead to new medications and potentially even gene therapy.
Cardiovascular disease is the leading cause of death in the United States, with nearly 1 million dying each year. Studies have shown that cardiovascular disease runs in families, suggesting that certain risk factors may be inherited. Lifestyle factors, such as smoking, lack of exercise, stress and diet, also appear to play a role.
Dr. Shuldiner says the Old Order Amish in Lancaster County, Pa., are ideal for genetic studies because they are a genetically homogenous people, tracing their ancestry back 14 generations to a small group of families who came to the United States from Europe in the mid-1700s. The Amish also have large families, keep detailed genealogical records and have a similar rural lifestyle.
But Dr. Shuldiner expects that the results of the study will not be limited to the Amish. We believe that our findings will apply to the general Caucasian population in the United States and Europe, and maybe even to a broader group of people as well, he says.
Dr. Shuldiner has studied the Amish in Lancaster County, Pa., since 1993, looking at various medical problems, such as diabetes, obesity and high blood pressure. He found that the incidence of Type 2 diabetes among the Amish is only about half that of the U.S. Caucasian population, although they have the same level of obesity. The Amish also have favorable cholesterol levels, even though their diet is high in fat and cholesterol. These differences may be due to lifestyle factors (the Amish are more physically active than non-Amish U.S. Caucasians), or genetic factors.
We know that cardiovascular disease exists in the Amish, but we don't know whether it is higher or lower or the same as in the general population, he says. This study should tell us not only if they have genes that help to prevent the disease, but also which genes they are.
The 1,000 people to be studied under the new grant are also taking part in the Amish Family Calcification Study, which is looking at bone density and coronary artery disease. As part of that study, researchers have performed 800 genetic tests throughout the entire genome in each of the participants. In the new cardiovascular study, Dr. Shuldiner and his co-investigators from the University of Maryland and the University of Michigan will use highly sophisticated computer programs to try to link these genes to cardiovascular changes resulting from lifestyle factors, such as a high-fat meal, low-salt diet or stress.
Researchers will take blood samples to retrieve DNA and to measure a person's cholesterol levels and blood-clotting ability before and after aspirin therapy. They will monitor blood pressure during a high-and low-salt diet and use ultrasound equipment to measure the ability of the main artery in the upper arm to dilate properly after the wrist and hand are immersed in ice water to simulate stress and later after a high-fat meal.
Dr. Shuldiner expects the study to get underway in early spring at the Amish Research Clinic in Strasburg, Pa. The $10.6 million grant will be spread out over four years, with $2.75 million earmarked for the first year.
The study is one of five projects funded by the National Heart, Lung and Blood Institute to investigate the interaction of genes and environmental factors in shaping risk factors for heart, lung, blood and sleep disorders.
The four other grants, to study different ethnic and racial groups, were awarded to researchers at the Johns Hopkins School of Medicine, the University of Minnesota School of Public Health in Minneapolis, the Pennington Biomedical Research Institute in Baton Rouge, La., and Tulane University School of Public Health and Tropical Medicine in New Orleans, La.
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