Large Gene Mapping Study Reveals DNA Loci Linked to Hypertension

Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure), and even small increments in blood pressure are associated with an increased risk of cardiovascular disease.

In two recent papers, members of the International Consortium for Blood Pressure Genome-Wide Association Studies have published results obtained by analyzing genetic data from over 275,000 individuals from around the world.

In the first paper, which was published the September 11, 2011, online edition of the journal Nature, they described the analysis of 2.5 million DNA sequence variants in more than 69,000 individuals of European ancestry. They identified several chromosomal regions where genes influencing blood pressure appeared to be located. Subsequently, researchers genotyped the strongest variants in more than 133,000 additional individuals of European descent. Combining the results yielded 28 gene regions associated with both systolic and diastolic blood pressure, of which 16 were novel. Six additional novel variants were reported in the September 11, 2011, online edition of the journal Nature Genetics.

The gene loci identified in these studies were associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. These associations with blood pressure were then confirmed by gene mapping of more than 74,000 individuals of East Asian, South Asian and African ancestry.

Three of the 28 blood-pressure-associated regions include genes that are part of the cyclic guanosine monophosphate (cGMP) pathway, which is involved in the relaxation of blood vessels and excretion of sodium by the kidneys, two fundamental mechanisms of hypertension treatment.

“Identifying these novel pathways expands our current understanding of the determinants of blood pressure and highlights potential targets for new drugs to treat and prevent cardiovascular complications," said contributing author Dr. Christopher Newton-Cheh, assistant professor of medicine at Harvard Medical School (Boston, MA, USA; www.med.harvard.edu). “We have previously shown that variants in natriuretic peptide genes, part of the cGMP system, influence blood pressure. We were therefore pleased but not surprised to see other genes that influence the cGMP system in this recent crop of discoveries.”

“Finding several independent associations that converge on cGMP points to its central importance in blood pressure control,” said Dr. Newton-Cheh. “In fact, there are several drugs that target these systems in development to treat pulmonary hypertension and heart failure, but our findings suggest that they could have a much larger role in hypertension treatment in general. The next phase of our research will focus on finding additional genes and variants that influence blood pressure and on establishing how some of the cGMP-involved genes affect blood pressure in humans and respond to existing drugs and to those in development.”

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