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Frustrating Search for Hypertension Genes Continues
Edward R. Winstead

Despite years of searching, researchers have yet to discover a human gene that controls blood pressure or contributes to hypertension. The worldwide effort has generated a list of chromosome regions that may contain these genes but no specific genes or variants.

Now, a region of chromosome 6 has been added to the list. British researchers discovered the region by “scanning” the genomes of 2,000 pairs of siblings from families with severe hypertension for DNA they had in common. In addition to chromosome 6, several other areas were implicated, but the statistical evidence was modest.

The next step is to screen the regions for gene candidates, but the researchers acknowledge that whatever they find will not be the whole story on the genetics of hypertension.

‘Where are all the blood-pressure genes?’

Indeed, the story seems to be that many genes (or variants) contribute in small degrees to inherited differences in blood pressure, and that different genes may confer risk for hypertension in different populations.

“We really don’t know how many blood pressure genes there are,” says Mark J. Caulfield of Queen Mary’s School of Medicine, London, who led the new study. “We hope they number 5 or 10, but there could be 20 or more.”

As with other complex diseases, like schizophrenia and heart disease, pinpointing genetic risk factors for hypertension will not be easy.

Consider a recent analysis of data from genome scans for hypertension genes published in the scientific literature. This “meta-analysis” found that no single chromosome region consistently had large effects on blood pressure or hypertension in all the study populations. It was published in the American Journal of Hypertension in February.

The original genome scans were done at medical centers in the United States as part of the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP). The subjects came from different ethnic groups and represented the racial diversity of the U.S. population.

The new research is part of the Medical Research Council’s BRItish Genetics of HyperTension (BRIGHT) study. The findings appear in The Lancet along with a commentary entitled “Where are all the blood-pressure genes?”

Citing the challenges of finding genes underlying common diseases, the commentary’s author, Stephen B. Harrap of the University of Melbourne, Australia, suggests that it simply may not be possible to discover gene variants for hypertension that would be valuable in the diagnosis of the disease.

Rather than search for every gene variant underlying hypertension, he argues, the field needs to “search for molecular clues to the common physiological mechanisms underlying disease.”

The study in The Lancet may ultimately lead to new risk factors for severe hypertension. None of the chromosome regions in the study was associated with the disease in humans until now. But part of chromosome 2 corresponds to a region of the rat genome associated with elevated blood pressure.

“We are encouraged by this because it means we may have found a region that actually contains genes” for hypertension, says Caulfield. “We’re making some progress, though perhaps not as much as we would like.”

“If finding the genes were easy, we would not have undertaken such large studies.”

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Caulfield, M. et al. Genome-wide mapping of human loci for essential hypertension. Lancet 361, 2118-2123 (June 21, 2003).
Harrap, S.B. Where are all the blood-pressure genes? Lancet 361, 2149-2151 (June 21, 2003).
Province, M.A. et al. A meta-analysis of genome-wide linkage scans for hypertension: The National Heart, Lung and Blood Institute Family Blood Pressure Program. American Journal of Hypertension 16, 144-147 (February 2003).

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