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Homing in on blood pressure genes may lead to targeted therapy

September 26, 2005

American Heart Association meeting report

WASHINGTON D.C. - For the first time, researchers have mapped a genetic location that explains why certain blood pressure-lowering drugs aren't effective for some people, according to researchers at the 2005 American Heart Association High Blood Pressure Research meeting.

"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.

Finding genes that determine a person's response to antihypertensive drugs is critical for effective therapy and also for understanding the cause of the disease, he said. According to American Heart Association, about 65 million Americans have high blood pressure and about 25 percent of them are on medication, but do not have it under control.

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. Once they know the location of the gene or genes, it will be easier to actually pinpoint them, Padmanabhan explained.

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.

The researchers then collected and analyzed DNA samples from all the siblings. 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.

"In other words, the same variation in genetic markers on chromosome 2 was significantly more likely to be found in the non-responders than in people who did respond to ACE inhibitors and beta blockers," Padmanabhan said.

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. "Knowing who will not respond to certain drugs will allow us to tailor treatment for maximum benefit and the least side effects," Padmanabhan said.

Co-authors are Chris Wallace, Ph.D.; Patricia B. Munroe Ph.D.; Morris Brown, F.R.C.P.; Nilesh Samani, F.R.C.P.; David Clayton, Ph.D.; Martin Farrall, Ph.D.; John Webster, F.R.C.P.; Mark Lathrop, Ph.D.; Mark Caulfield, F.R.C.P.; Anna F. Dominiczak, F.R.C.P.; and John M. Connell, F.R.C.P.

American Heart Association