Homing In On Blood Pressure Genes May Lead To Targeted Therapy

"The findings bring us a step closer to developing targetedtherapies for patients with high blood pressure who might otherwise bestarted on medications that won't help," said lead author SandoshPadmanabhan, Ph.D., specialist registrar at the British HeartFoundation Glasgow Cardiovascular Research Centre at the University ofGlasgow in Scotland.

Finding genes that determine a person's response toantihypertensive drugs is critical for effective therapy and also forunderstanding the cause of the disease, he said. According to AmericanHeart Association, about 65 million Americans have high blood pressureand about 25 percent of them are on medication, but do not have itunder 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, heartattack, heart failure and/or kidney failure. The World HealthOrganization estimates that suboptimal blood pressure is responsiblefor 62 percent of cerebrovascular disease and 49 percent of ischemicheart disease.

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

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

The research team from the United Kingdom studied a largegroup of severely hypertensive Caucasian families to try to identifythe location of some of these genes. Once they know the location of thegene or genes, it will be easier to actually pinpoint them, Padmanabhanexplained.

The investigation (MRC Bright Study) included 2,142 Caucasianfamilies with severe hypertension. The researchers noted what drugs thestudy participants were taking to control their hypertension andmeasured their blood pressure after treatment.

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

The researchers then collected and analyzed DNA samples fromall the siblings. Using genome-wide linkage analysis, they located aregion on chromosome 2 that appears to be involved in causing highblood pressure in people who do not respond to ACE inhibitors and betablockers.

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

African Americans, not Caucasians, typically havesalt-sensitive high blood pressure that does not respond to ACEinhibitors and beta blockers, he said. And coincidentally, a recentAmerican study showed that high blood pressure in African Americansmaps to this exact same chromosome region.

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

The next step, he said is to pinpoint the exact mutant geneor genes responsible for this drug response. "Knowing who will notrespond to certain drugs will allow us to tailor treatment for maximumbenefit 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.

The Medical Research Council funded the research.