Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rare genetic mutations protect against hypertension

08.04.2008
Howard Hughes Medical Institute (HHMI) researchers have found that rare mutations in three genes contribute to blood pressure variation in the general population.

The scientists had previously shown that mutations in the three “salt handling” genes cause several rare diseases that are characterized by low blood pressure. By sequencing DNA samples obtained from 3,125 people who are participating in the Framingham Heart Study, the researchers identified new functional mutations in these three genes that are likely to be carried by an estimated 100 million people worldwide.

The Framingham Heart Study was begun in 1948 in an effort to identify common factors or characteristics that contribute to cardiovascular disease by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke.

“We find that about two percent of the population has mutations in at least one of these three genes – although all of the identified mutations are individually very rare,” said senior author Richard P. Lifton, a Howard Hughes Medical Institute researcher at Yale University School of Medicine. “Mutation carriers have reduced blood pressure, with a 60 percent reduction in the risk of hypertension at age 60.”

The findings, reported in the April 6, 2008, edition of the journal Nature Genetics, are important because they yield tantalizing new evidence about why some people seem to be less susceptible to developing high blood pressure, a condition that affects a billion people worldwide and contributes significantly to heart and kidney disease, and stroke.

What's more, by identifying the role played by rare genetic mutations in governing how the kidney regulates salt, the researchers have devised a general approach that may be broadly applicable to uncovering the genetic architecture of common conditions such as hypertension.

“This new study, for the first time, extends the findings from patients with rare Mendelian traits to the general population. The findings suggest that independently rare mutations that alter salt handling by the kidneys collectively account for a substantial fraction of the general population's variability in disease susceptibility,” said Lifton.

Lifton noted that there are probably about 100 million people worldwide who carry the mutations and are thus protected from hypertension. “The mutations we have identified have clinically meaningful effects to individual patients and suggest that independently rare mutations will collectively account for a substantial fraction of the population's variability in disease susceptibility,” he said.

The researchers started by examining variations in three genes known to cause rare recessive diseases characterized by large reductions in blood pressure. The analysis was conducted on “salt handling” genes isolated from people involved in the Framingham Heart Study (FHS), which is directed by Daniel Levy of the National Heart, Lung and Blood Institute. Levy is a co-author of the Nature Genetics report. Co-first authors Weizhen Ji and Jia Ni Foo are at Yale University School of Medicine.

Lifton's team zeroed in on the three salt-regulating genes -- NCCT, NKCC2 and ROMK -- which his group had previously linked to rare but serious human diseases, including Gitelman and Bartter syndromes. Both are conditions characterized by inherited low blood pressure caused by recessive mutations, where two defective copies of a gene are at play.

Salt handing is an essential function of the kidneys. Our kidneys process more than three pounds of salt per day, and genetic mutations that raise or lower the ability of the organ to absorb and process salt can manifest themselves in higher or lower blood pressure.

Lifton's group has searched worldwide for patients with very high or very low blood pressure due to mutations in single genes. Such patients are often identified through family histories of extreme blood pressure. To date, his group has found a score of gene mutations that lower or raise blood pressure, including those that cause the extreme low blood pressure found in patients with Gitelman and Bartter syndromes.

“We used knowledge of the spectrum of mutations that cause Gitelman and Bartter syndromes to sort among the hundreds of sequence changes we observed to identify those that are either known or highly likely to alter the function of the (gene) encoded proteins,” Lifton explained.

By sequencing each of the three genes obtained from DNA samples from 3,125 participants in the Framingham Heart Study, and doing additional biochemical, genetic and genomic analysis, the HHMI team found functional mutations in one of the genes in at least 1 of every 64 of the study's participants sampled.

“The results show that nearly 2 percent of the FHS cohort has a defective copy of one of these three genes,” Lifton said. “Unlike patients with Gitelman and Bartter syndromes, these subjects have only one defective copy, not two.”

Lifton's group then tracked the influence of the mutation on blood pressure in FHS subjects aged 40-60, a time of life when hypertension manifests itself and can pose serious health risks.

“We found that these mutation carriers have a 60 percent reduction in their risk of developing hypertension” and have significantly lower blood pressure than those who do not have mutations,” Lifton said. The influence of the mutation, he added, approximates effects achieved with drugs used to lower blood pressure.

The practical upshot of the new work, according to Lifton, could be potential new drugs to mimic the effects of the mutation by selectively inhibiting a single gene or several genes.

In addition, the study more broadly underscores the value of genetic analysis -- resequencing of genes and genomes to ferret out functional mutations -- for understanding individual risk of disease.

“A major question about the genetic underpinnings of hypertension and other common diseases has been whether these are accounted for by common or rare DNA variations,” said Lifton. “Our study demonstrates the role of rare variation, showing that effects of rare mutations in these three genes cause relatively large effects, with clinically significant effects in individual patients. These findings suggest that much of the variation in common disease risk for hypertension and other diseases will be accounted for by rare (genetic) variants.”

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Health and Medicine:

nachricht Enabling technology in cell-based therapies: Scale-up, scale-out or program in-place
23.07.2018 | SLAS (Society for Laboratory Automation and Screening)

nachricht FAU researchers identify Parkinson's disease as a possible autoimmune disease
23.07.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Detecting damage in non-magnetic steel with the help of magnetism

23.07.2018 | Materials Sciences

Researchers move closer to completely optical artificial neural network

23.07.2018 | Information Technology

Enabling technology in cell-based therapies: Scale-up, scale-out or program in-place

23.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>