Chromosome 2 region linked to ACE inhibitors & beta blockers non-responders
Sep 24, 2005 - 3:38:38 PM

For the first time, researchers have mapped a genetic location that explains why certain blood pressure-lowering drugs aren't effective for some people.

"The findings bring us a step closer to developing targeted therapies for patients with high blood pressure who might otherwise be started on medications that won't help," said lead author Sandosh Padmanabhan, Ph.D., specialist registrar at the British Heart Foundation Glasgow Cardiovascular Research Centre at the University of Glasgow in Scotland.

Goal blood pressure is less than 140/90 mm Hg, or less than 130/80 mm Hg for those with diabetes or kidney disease.

Uncontrolled high blood pressure can lead to stroke, heart attack, heart failure and/or kidney failure. The World Health Organization estimates that suboptimal blood pressure is responsible for 62 percent of cerebrovascular disease and 49 percent of ischemic heart disease.

The cause of 90 percent to 95 percent of the cases of high blood pressure isn't known, but is likely to be due to multiple genes and environmental factors.

Researchers have been trying to identify genes responsible for high blood pressure. But most studies have been inconclusive, "probably because so many genes are working together," Padmanabhan said.

The research team from the United Kingdom studied a large group of severely hypertensive Caucasian families to try to identify the location of some of these genes. The investigation (MRC Bright Study) included 2,142 Caucasian families with severe hypertension. The researchers noted what drugs the study participants were taking to control their hypertension and measured their blood pressure after treatment.

The researchers identified 89 sibling pairs who did not respond to ACE inhibitors and beta blockers and 76 sibling pairs who did not respond to calcium channel blockers and diuretics. For purposes of the study, lack of response was defined as a failure to reach target blood pressure levels of 140/90 mm Hg or a reduction in blood pressure of less than 20 points.

Using genome-wide linkage analysis, they located a region on chromosome 2 that appears to be involved in causing high blood pressure in people who do not respond to ACE inhibitors and beta blockers.

African Americans, not Caucasians, typically have salt-sensitive high blood pressure that does not respond to ACE inhibitors and beta blockers, he said. And coincidentally, a recent American study showed that high blood pressure in African Americans maps to this exact same chromosome region.

Taken together, "the studies show that there is a strong likelihood that this region on the short arm of chromosome 2 may contain the gene or genes responsible for a salt-sensitive form of hypertension that is unresponsive to ACE inhibitors and beta blockers," Padmanabhan said.

The next step, he said is to pinpoint the exact mutant gene or genes responsible for this drug response.

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