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International Consortium Discovers New Blood Pressure Risk Loci

NEW YORK (GenomeWeb News) – Two new genome-wide association studies have uncovered genetic loci influencing several blood pressure traits, including systolic and diastolic pressure, pulse pressure, and mean arterial pressure.

In the first of these studies, members of the International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) from two-dozen countries tracked down 28 risk loci influencing systolic and/or diastolic blood pressure through a multi-phase GWAS meta-analysis and genotyping study on some 200,000 individuals of European descent. At least some of the loci were subsequently linked to blood pressure patterns in individuals from Asian and African populations as well.

When they tested a blood pressure risk score based on 29 independent variants at the 28 associated loci in nearly 23,300 women, they found links to hypertension, heart disease, stroke risk, and more. On the other hand, the variants did not help in discerning kidney function or disease risk. The group reported their findings online yesterday 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," co-corresponding author Aravinda Chakravarti, a pediatric, molecular biology, and genetics researcher at Johns Hopkins University, said in a statement.

The research team used genotyped or imputed data at roughly 2.5 million SNPs in 69,395 individuals of European descent enrolled through 29 past studies to look for variants coinciding with blood pressure patterns.

In particular, they focused on systolic pressure, the pressure exerted on arteries when the heart pumps, diastolic blood pressure, measured when the heart muscle relaxes, and hypertension, a condition characterized by systolic and/or diastolic blood pressure that's consistently higher than the normal range.

When they tested the most promising SNPs from the first stage of the study in another 133,661 individuals of European ancestry, the researchers were left with 29 blood pressure-related SNPs at 28 loci. Sixteen of the sites had not been implicated in blood pressure control in the past, although six of the new loci did fall in or around genes or pathways suspected of contributing to blood pressure-related processes.

Follow up studies on tens of thousands of non-Europeans, including 29,719 East Asians, 23,977 South Asians, and 19,775 Africans, suggested that nine of the loci are also associated with blood pressure in East Asian populations, while six showed significant associations in the South Asian group.

Each associated variant had a small effect on systolic or diastolic blood pressure overall, the study authors reported. But a weighted risk score comprised of data at all 29 sites in the genome did offer a window into hypertension risk — and the risk of related conditions such as thickening of the heart's left ventricle, stroke, or coronary artery disease. In contrast, the risk score did not provide clues about kidney function or kidney disease.

"The absence of association with kidney phenotypes could be explained by a weaker causal relationship between blood pressure and kidney phenotypes than with [coronary artery disease] and stroke," the study authors explained. "[S]everal lines of evidence converge to indicate that blood pressure elevation may in part be a consequence rather than cause of sub-clinical kidney disease."

In another GWAS in the early, online version of Nature Genetics, meanwhile, ICBP-GWAS researchers used another large GWAS meta-analysis to track down six previously undetected regions of the genome that appear to influence two more blood pressure measures: pulse pressure and mean arterial pressure.

"Our study shows the importance of looking at different measures of blood pressure in order to identify new genetic variants that affect levels of blood pressure in the population," co-first author Louise Wain, a University of Leicester researcher, said in a statement.

For that study, researchers initially did a meta-analysis of genotyping data for 74,064 European individuals, including many of the same participants evaluated in the Nature study, before following up on candidate variants in tens of thousands more study participants.

In the process, the team found pulse pressure-associated loci that reached genome-wide significance on chromosomes 4, 7, 8, and 11 and two sites on chromosomes 3 and 10 with genome-wide significant associations with mean arterial pressure.

The search also uncovered one locus linked to both pulse pressure and mean arterial pressure, they reported — a chromosome 2 site implicated in systolic blood pressure control in individuals of East Asian ancestry.

"Our findings show that analyses of [pulse pressure] and [mean arterial pressure] identify loci influencing blood pressure phenotypes that may not be detectable by studying [systolic blood pressure] and [diastolic blood pressure] separately," researchers wrote.

Even so, they reported, while many of the loci seem to influence systolic and diastolic blood pressure patterns in the same way, at least three pulse pressure-associated regions appear to have opposing influences on systolic and diastolic traits.

There's still more to learn about how the newly detected genetic variants contribute to blood pressure biology. And researchers suspect there are many more genetic factors that haven't been identified yet. Nevertheless, the studies are helping to flesh out a picture of how some of the pathways interact to produce various blood pressure patterns.

"[B]lood pressure is a function of these genes we just identified as well as perhaps a hundred others we haven't found yet," Chakravarti said in a statement. "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."

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