October 31, 2011
Genomewide hunts reveal new regulators of blood pressure
A study involving more than 200,000 people worldwide has identified 29 DNA sequence variations in locations across the human genome that influence blood pressure. These genes, whose sequence changes are associated with alterations in blood pressure and are linked to heart disease and stroke, were found with the help of decades’ worth of population data that were pooled and analyzed by a large international consortium, including Johns Hopkins researchers.
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 Sept. 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,” said Aravinda Chakravarti, 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 had their blood pressures recorded when they 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 genomewide association study focused on systolic and diastolic blood pressures, measures of the maximum and minimum pressures exerted on the arteries. However, in a related genomewide investigation reported Sept. 11 in Nature Genetics, some of 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 genomewide 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 said. “The more ways we search for blood pressure genes, the better our ability to understand hypertension, whose effects 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 Health Study, started in 1989; and the Atherosclerosis Risk in Communities 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,” said 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 genomewide 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, or SNPs, throughout the genome. SNPs, pronounced “snips,” 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,” Chakravarti said. “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 Heart, Lung and Blood Institute, and European and private funding agencies.
More than 230 scientists contributed to the Nature study; Chakravarti is a corresponding author. The lead author is Georg B. Ehret, also of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. 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 are Ehret and Pihur.