September 12, 2011
Findings on blood pressure and heart disease genetic risk include UW research contributions
Major advances on the genetics of blood pressure and cardiovascular disease will be reported Sunday, Sept. 11, in the journal Nature. The International Consortium for Blood Pressure Genome-Wide Association Studies has identified common genetic variants associated with blood pressure in 28 regions on the human genome.
More than one billion people in the world have high blood pressure greater than 140/90. The condition increases the risk of stroke or heart attack.
Scientists from the University of Washington played key roles in analyzing the massive amounts of data collected for the study, as well as in gathering genetic and clinical information for the project.
The UW researchers were Ken Rice, associate professor of biostatistics, UW School of Public Health; Bruce M. Psaty, professor of medicine and epidemiology and co-director of the Cardiovascular Health Research Unit; Joshua C. Bis, research scientist /engineer, Division of General Internal Medicine, Department of Medicine; Susan R. Heckbert, professor of epidemiology; Nicholas L. Smith, epidemiologist, and Kerri Wiggins, data manager/analyst, both at the Cardiovascular Health Research Unit; and William T. Longstreth, professor of neurology.
They were among the 346 scientists from more than 200 centers in 24 countries who conducted the research.
The study included more than 200,000 individuals of European descent.
“For each of these people, our study recorded the persons genotype, that is, which genetic letter (A, C. G, T) occurred at 2.5 million locations along his or her DNA,” explained Rice, who was one of the lead authors on the paper. “By finding locations where people with unusually high or low blood pressure have some particular letter, we learn which genes affect blood pressure. These are the Nature papers big results.”
“Most of these genes were not previously known to act in this way, so were learning a lot of new biology about how blood pressure works,” Rice noted. In the future, this knowledge may help us design better treatment for high blood pressure and perhaps ultimately help prevent strokes, heart disease and early deaths.”
Using the collective information from these 26 regions of the genome, researchers were able to assign a genetic risk score for high blood pressure, heart disease and stroke. The score is based on the individuals profile for 26 genetic variants across the genome. This genetic risk score also was associated with blood pressure in individuals of East Asian, South Asian, or African ancestry.
Rice added that eventually clinicians might be able to review their patients genotypes to see if they are predisposed to blood pressure problems, and to suggest which treatments might work best for them, tailored to the specific gene variants the individual has inherited.
Even in healthy people, maintaining a safe blood pressure requires constant adjustment for such simple changes as rising from a chair. The findings provide new insights into the biology of blood pressure regulation. For example, a couple of genes encode for substances that the hearts blood vessels turn into a peptide that flushes sodium into the urine. Another location on the genome encodes for a chemical that dilates the blood vessels. Other locations contain genes active in zinc, cadmium, and manganese transport, and possibly in cholesterol levels as well.
Although a significant portion of people with high blood pressure develop kidney disease, the researchers found no statistical association between the newly devised genetic risk score and kidney function or chronic kidney disease. The lack of a link could suggest that high blood pressure might be a consequence rather than a cause of kidney disease, or that any causal relationship might be more subtle than that between hypertension and cardiovascular disease, according to the researchers. This viewpoint is supported, they noted, by inconsistent evidence from other studies on whether lowering high blood pressure prevents kidney disease.
The almost unprecedented amount of data generated for the blood pressure gene association study, Rice said, made ensuring that the statistical analysis was appropriate a daunting enterprise
“Some of the difficulty is just in the bookkeeping – keeping track of the genotype and blood pressure connections seen in 200 plus small studies in 24 countries, so that over several stages we can pool them together to form one huge study, known as a ‘meta-analysis.”
Another stumbling block is that the gene effects are small, Rice explained. Each gene effect is at least one order of magnitude smaller than the effect of taking anti-hypertensive drugs.
“We have to pick out the genes with ‘signals from all of the ‘noise at the millions of other locations on the genome that dont affect blood pressure,” Rice noted, adding, “It is surprisingly hard to do this right; the results are easily overstated.”
In addition to assisting with the statistical analysis, the UW had investigators in several other important roles in the project. Some of the data came from the UW-based Cardiovascular Health Study, part of the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium, through which many prior genome-wide studies have been done. In addition, members of the UW Cardiovascular Health Research Unit provided epidemiological expertise and experience gained from work on similar, smaller studies. They considered, among other things, the influence of different ages, geographical locations, ethnicities, and ways of life represented in the different contributing studies. For example, the United States portions contained data from genetic and health studies of Amish and other distinct groups, as well as from diverse mainstream America.
“Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk” was funded by many governments, private foundations, and industries throughout the world.
The researchers extend their gratitude to all of the individuals, families, and communities around the globe who participated in this international collaboration.