Genome-wide hunts reveal new regulators of blood pressure; Genetic variants linked to increased risk of hypertension, stroke and other cardiovascular diseases

Among the findings was evidence that the same common genetic variants associated with hypertension in European populations also are frequently found in individuals of Asian and African ancestry, according to the report that appears September 11 in Nature.

"A genetic risk score that adds up the effects of all of these variants shows that the more of these variants an individual has, the greater are his or her chances of having hypertension, left ventricular wall thickness, stroke and coronary artery disease," says Aravinda Chakravarti, Ph.D., a professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, and one of the lead authors.

The individuals whose genomes were analyzed for this study had their blood pressures recorded when they originally entered other long-term cardiovascular research studies, and scientists used these measures to assess the predictive value of the genes and blood pressures in terms of the subjects' current cardiovascular status.

This genome-wide association study focused on systolic and diastolic blood pressures: measures of the maximum and minimum pressures exerted on the arteries. However, in a related genome-wide investigation reported September 11 in Nature Genetics, the same scientists found an additional six locations across the genome where variants affect blood pressure by focusing on two other relevant measures: pulse pressure (the difference between systolic and diastolic blood pressure) and mean arterial pressure (a weighted average of systolic and diastolic blood pressure). The group conducted a genome-wide association meta-analysis of pulse pressure and mean arterial pressure in 74,064 individuals of European ancestry from 35 studies and then followed up the results in 48,607 additional individuals.

"It's like using four different cops to find the same culprit," Chakravarti says. "The more ways we search for blood pressure genes, the better our ability to understand hypertension, whose affects are not uni-causal."

For the billion-plus people worldwide with hypertension, even small elevations in blood pressure are associated with increased risk of cardiovascular disease. Although it's generally known that hypertension has a familial component, the genetic regulatory mechanisms of blood pressure have been challenging to pin down so far, Chakravarti says, citing similar genetic studies three years ago that failed to detect any genes. He credits the recent spate of genetic discoveries -- more than 300 genes for cardiovascular diseases have been identified in just the last few years -- to the collective analyses of long-term prospective research efforts such as the pioneering Framingham Heart Study, begun in 1948, the Cardiovascular Heath Study, started in 1989, and the Atherosclerosis Risk in Communities (ARIC) study, started in 1987.

"Too often, people look at these studies that have a long provenance and wonder what is it doing for them today," says Chakravarti, who compares the studies to a retirement account. "Researchers visit them time and time again. Without them, this feat of genetic studies would be impossible."

Each genome-wide association study, often referred to as GWAS, reported what effects were observed at which locations on the genome in a scan of single nucleotide polymorphisms (SNPs) throughout the genome. Pronounced snips, SNPs are sites where a single letter in the DNA code is variable between humans.

"Your blood pressure is a function of these genes we just identified as well as perhaps a hundred others we haven't found yet," says Chakravarti. "By revealing the genetic architecture of blood pressure, both studies will help us to understand the biology of cardiovascular diseases and stroke, and, eventually, may lead to better therapies."

Support for the international, multi-institutional project came from many funding mechanisms, including the National Institutes of Health National Heart, Lung and Blood Institute as well as European and private funding agencies.

Of more than 230 scientists who contributed to the Nature study, Chakravarti is a corresponding author. The lead author is Georg B. Ehret, also of the institute. Other Johns Hopkins authors are Vasyl Pihur, Josef Coresh, Judith A. Hoffman-Bolton, Linda Kao, Anna Kottgen, and J.Hunter Young.

In addition to Chakravarti, Johns Hopkins scientists who contributed to the Nature Genetics study include Georg B. Ehret and Vasyl Pihur.