May 17, 2010 (New York, New York) — A good-natured debate about whether genome-wide association studies (GWAS) will eventually help unravel the genetic basis of human hypertension entertained many here at the recent American Society of Hypertension 2010 Scientific Meeting.

Arguing that such studies have "cost millions of dollars" but failed to live up to expectations in the field of hypertension, Dr Theodore W Kurtz (University of California, San Francisco) said that it was time to put a stop to further GWAS: "They have taught us little about the genetics, pathophysiology, or treatment of hypertension.

Dr Anna Dominiczak (University of Glasgow, UK), taking the opposing position, said that although it is true that GWAS have so far only yielded a few genetic variants, which explain a very small proportion of the total variation in blood pressure, "the best is yet to come."

Next Step: From Genetic Localization to Medically Useful Applications

Dominiczak said GWAS in hypertension "have not played out like GWAS in other complex disorders," because hypertension "is even more complex." Nevertheless, two large-scale meta-analyses of GWAS for blood pressure and hypertension, published last year, both identified significant associations at a number of genetic loci, she told the meeting.

"We do have reproducible, sturdy, robust polymorphisms responsible for common garden-variety hypertension," she noted. She also pointed out that although Kurtz might argue that these represent small effects of multiple genes, "the aggregate effects of several variants do produce meaningful population changes in risk."

The search is now on for lower-frequency variants that will have bigger effects on blood pressure: "What the earlier GWAS did was show us where to look for these," she explained.

The next challenge will be to develop research methods "to transport us from genetic localization to medically useful applications," such as drug targets, she noted, adding that other aspects of genomic research will undoubtedly play a role in this, such as copy number variants, metabolomics, and epigenetics.

Science "Never Works Out Like You Imagine It"

Kurtz explained he was taking a stance against GWAS in hypertension, "not just to play devil's advocate, but because I firmly believe the points I am making."

GWAS have failed to show associations with any of the known targets used for treating hypertension today. Even if every genetic factor involved in hypertension could be identified and analyzed, the accuracy of genetic profiling would be "no better than simple clinical risk scores in predicting who will and will not get hypertension," he argued.

In most cases, the genes and regions identified are novel and fill critical gaps in our knowledge.

But Dominiczak said that Kurtz misunderstands the goals. "The challenge is to attach function to our findings, to help in the understanding and the pathophysiology of hypertension, not to develop risk stratification. In most cases, the genes and regions identified are novel and fill critical gaps in our knowledge," she maintained. "There are drugs hiding in there. We just need to follow our studies to get to function."

Kurtz retorted that Dominiczak was "backing away from the original claims" made by GWAS researchers," that is, the whole concept of personalized medicine." With the advent of other genomic technologies, such as the spectacular advances in DNA sequencing techniques, he predicted, "GWAS will not unlock the genetic basis of human hypertension."

Asked by heartwire whether things had worked out as she imagined with regard to GWAS in hypertension, Dominiczak said: "Science never works like you would have first imagined it, never ever. We went into this with our eyes open that it was going to be difficult, and it's artificial for the debate to just take one technology and consider it in isolation from the rest. It's two, three, and four genomic and postgenomic technologies that need to come together, so I am not disappointed at all."

Kurtz, she said, "sees the glass as half empty; I see it as half full."

Continue These Genetic Studies

Asked to comment, European Society of Hypertension president Dr Krzysztof Narkiewicz (Medical University of Gdansk, Poland) told heartwire : "I thought it was an excellent debate. Maybe the expectations were a bit too high 10 years ago, but I think overall there is still some progress and we have learned a lot, step-by-step."

"I think the main message is that we should continue these genetic studies. We have somehow to adjust the methods we use, and the results may take 20 more years, maybe less, to get into clinical practice, but this is the way to go," he concluded.

Kurtz and Dominiczak report no conflicts of interest. Narkiewicz reports being a speaker for Abbott, AstraZeneca, Berlin Chemie Menarini, Boehringer Ingelheim, Daiichi-Sankyo, Krka, Novartis, and Servier.


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