Scientists from Massachusetts General Hospital (MGH), as part of a major international research collaboration, have associated common variants in eight regions of DNA with blood pressure levels in human patients. Six of the identified regions have not previously been implicated in blood pressure regulation. In their study, receiving advance online publication in Nature Genetics, members of the Global Blood Pressure Genetics (Global BPgen) consortium - which includes 159 investigators from 93 centers in the U.S. and Europe - analyzed genetic data from up to 130,000 individuals from around the world.
"This is a major advance because it identifies novel pathways that may expand our current understanding of the determinants of blood pressure and highlight potential targets for new drugs to treat or possibly even prevent hypertension," says Christopher Newton-Cheh, MD, MPH, of the Massachusetts General Hospital (MGH) Center for Human Genetic Research and Cardiovascular Research Center, first and co-corresponding author of the report. Results from the Global BPgen study and a similar investigation from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, also appearing in Nature Genetics, are being presented on May 8 at the American Society for Hypertension annual meeting's late-breaking news research session in San Francisco.
High blood pressure or hypertension is a major risk factor for heart attack, stroke, heart failure and kidney failure. It is well known that hypertension can run in families and that some rare genetic syndromes raise blood pressure, but identifying genes associated with the common form of hypertension has been challenging since so many factors influence blood pressure. To get a study sample large enough to detect gene variants with modest effects, Global BPgen researchers conducted a meta-analysis of 17 genome-wide association studies that included measurements of participants' blood pressure. Analysis of 2.5 million DNA sequence variants in more than 34,000 individuals of European ancestry identified several chromosomal regions where genes influencing blood pressure appeared to be located.
To confirm the results of the first stage meta-analysis, two additional analyses were done. The researchers genotyped the 12 gene variants with the strongest signals in more than 71,000 additional individuals of European descent and in 12,300 people of Indian Asian ancestry. They also exchanged their top results with CHARGE consortium investigators.
Combining the results of all three analyses identified eight gene regions associated with both systolic and diastolic blood pressure and with the risk of hypertension. One region includes genes for two natriuretic peptides, proteins known to relax blood vessels and control sodium excretion by the kidneys. Earlier this year, another team led by Newton-Cheh found that variations in these proteins influence blood pressure, the first validated association of blood pressure with any common gene variants.
"We were pleased to replicate the natriuretic peptide variant association in the Global BPgen paper, but we cannot yet say whether there may be a second association in the same region," Newton-Cheh notes. Another region identified in the current study is known to contain a gene involved in a rare familial form of hypertension, but the other six regions had no previous association with blood pressure levels.
"These findings suggest exciting new avenues for blood pressure treatments that have not been explored because we had no way of knowing the gene regions were involved in blood pressure regulation," says Newton-Cheh, an assistant professor of Medicine at Harvard Medical School. "The next phase of our research will focus on finding which genes in these regions are causal, clarifying how they lead to changes in blood pressure and determining how those effects can be modified."
Additional co-corresponding authors of the Nature Genetics paper are Gonçalo Abecasis, DPhil, University of Michigan School of Public Health; and Mark Caulfield, MBBS, MD, FRCP, and Patricia Munroe, MSc PhD, both of the William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London. Support for the study came from nearly 100 governmental, charitable, and commercial organizations in the U.S. and Europe, including the National Institutes of Health, the Doris Duke Charitable Foundation and the Burroughs Wellcome Fund.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.