Researchers at the University of Maryland School of Medicine have identified a common gene variant that appears to influence people’s risk of developing high blood pressure, according to the results of a study being published online Dec. 29, 2008 in the Proceedings of the National Academy of Sciences (PNAS).

The STK39 gene is the first hypertension susceptibility gene to be uncovered through a new technique called a genome-wide association study and confirmed by data from several independent studies.  Located on chromosome 2, the gene produces a protein that helps to regulate how the kidneys process salt, which plays a key role in determining blood pressure.

“This discovery has great potential for enhancing our ability to tailor treatments to the individual – what we call personalized medicine – and to more effectively manage patients with hypertension.  We hope that it will lead to new therapies to combat this serious public health problem worldwide,” says the senior author, Yen-Pei Christy Chang, Ph.D., an assistant professor of medicine and of epidemiology and preventive medicine at the University of Maryland School of Medicine.

But, Dr. Chang says, more research is needed.  “Hypertension is a very complex condition, with numerous other genetic, environmental and lifestyle factors involved.  The STK39 gene is only one important piece of the puzzle,” she says.  “We want to determine how people with different variations of this gene respond to diuretics and other medications, or to lifestyle changes, such as reducing the amount of salt in their diet.  This information might help us discover the most effective way to control an individual patient’s blood pressure.”

One in four Americans has elevated blood pressure, or hypertension, which can lead to death or result in complications, such as cardiovascular disease, stroke and end-stage kidney disease.  Doctors consider the ideal systolic and diastolic blood pressure to be less than 120/80.  (The numbers reflect the pressure of the blood against the arteries when the heart beats and is at rest.)  When blood pressure is elevated, doctors recommend lifestyle changes or prescribe medications, such as diuretics, which force the kidneys to remove water from the body, in order to treat the condition.

However, patients respond differently to treatments and finding the best treatment among all the possible ones for specific patients is still a “try and see” process, according to Dr. Chang.

Scientists believe multiple genes are involved in the most common form of high blood pressure called essential hypertension.  But, because so many factors affect blood pressure, including diet, exercise and stress levels, it has been difficult to pinpoint a specific gene or group of genes, says the lead author, Ying Wang, Ph.D., a researcher at the University of Maryland School of Medicine.

The University of Maryland researchers identified the link between the STK39 gene and blood pressure by analyzing the DNA of 542 members of the Old Order Amish community in Lancaster County, Pa., scanning approximately 100,000 genetic markers across the entire genome for variants known as single nucleotide polymorphisms, or SNPs, associated with systolic and diastolic blood pressure.  The researchers found strong association “signals” with common variants of the serine/threonine kinase gene, or STK39, and confirmed their findings in another group of Amish people and in four other groups of Caucasians in the United States and Europe.

People with one particular variant showed slight increases in blood pressure compared to those with a more common form of the gene and were more likely to develop hypertension, researchers found.  The researchers estimate that about 20 percent of Caucasians in the general population have this variant of the STK39 gene.

“With this new ’scanning’ approach – the genome-wide association study – we are able to uncover genes that have previously eluded us.  The field of complex disease genetics has undergone a revolution in terms of discovering new genes and understanding the genetic basis of common adult-onset diseases,” says co-author Alan R. Shuldiner, M.D., professor of medicine; head of the Division of Endocrinology, Diabetes and Nutrition; and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine.

The study being published online in PNAS is titled, “Whole-genome association study identifies STK39 as a novel hypertension susceptibility gene.”  It will appear in the print edition of PNAS early next month.

The Amish are ideal for such studies because they are a genetically homogeneous people whose forefathers came to Pennsylvania from Europe in the mid-1700s and share a similar diet and rural lifestyle.  Because many in the Amish community don’t have regular medical check-ups, they often don’t know they have high blood pressure or take medications for it, according to Dr. Chang.  The Amish appear to have as much hypertension as other Caucasians.  As a result of the study, some of the participants learned that they had hypertension and were able to start treatment.

The research, which was funded by the National Institutes of Health, is a spin-off project of another University of Maryland study – the Amish Family Diabetes study – looking for genes that may cause type 2 diabetes.  Researchers at the School of Medicine already have identified a number of genes that may play a role in the development of this type of diabetes.

Facial expressions of emotion are hardwired into our genes, according to a study published today in the Journal of Personality and Social Psychology.  The research suggests that facial expressions of emotion are innate rather than a product of cultural learning.  The study is the first of its kind to demonstrate that sighted and blind individuals use the same facial expressions, producing the same facial muscle movements in response to specific emotional stimuli.

The study also provides new insight into how humans manage emotional displays according to social context, suggesting that the ability to regulate emotional expressions is not learned through observation.

San Francisco State University Psychology Professor David Matsumoto compared the facial expressions of sighted and blind judo athletes at the 2004 Summer Olympics and Paralympic Games.  More than 4,800 photographs were captured and analyzed, including images of athletes from 23 countries.

“The statistical correlation between the facial expressions of sighted and blind individuals was almost perfect,” Matsumoto said.  “This suggests something genetically resident within us is the source of facial expressions of emotion.”

Matsumoto found that sighted and blind individuals manage their expressions of emotion in the same way according to social context.  For example, because of the social nature of the Olympic medal ceremonies, 85 percent of silver medalists who lost their medal matches produced “social smiles” during the ceremony.  Social smiles use only the mouth muscles whereas true smiles, known as Duchenne smiles, cause the eyes to twinkle and narrow and the cheeks to rise.

“Losers pushed their lower lip up as if to control the emotion on their face and many produced social smiles,” Matsumoto said.  “Individuals blind from birth could not have learned to control their emotions in this way through visual learning so there must be another mechanism.  It could be that our emotions, and the systems to regulate them, are vestiges of our evolutionary ancestry.  It’s possible that in response to negative emotions, humans have developed a system that closes the mouth so that they are prevented from yelling, biting or throwing insults.”

New research in an animal model suggests that a diet high in inorganic phosphates, which are found in a variety of processed foods including meats, cheeses, beverages, and bakery products, might speed growth of lung cancer tumors and may even contribute to the development of those tumors in individuals predisposed to the disease.

The study also suggests that dietary regulation of inorganic phosphates may play an important role in lung cancer treatment.  The research, using a mouse model, was conducted by Myung-Haing Cho, D.V.M., Ph.D., and his colleagues at Seoul National University, appears in the first issue for January of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

“Our study indicates that increased intake of inorganic phosphates strongly stimulates lung cancer development in mice, and suggests that dietary regulation of inorganic phosphates may be critical for lung cancer treatment as well as prevention,” said Dr. Cho.

Lung cancer is the number one cause of cancer deaths in the world and is also the most frequently diagnosed solid tumor.  Non–small cell lung cancer (NSCLC) constitutes over 75 percent of lung cancers and has an average overall 35-year survival rate of 14 percent.  Earlier studies have indicated that approximately 90 percent of NSCLC cases were associated with activation of certain signaling pathways in lung tissue.  This study revealed that high levels of inorganic phosphates can stimulate those same pathways.

“Lung cancer is a disease of uncontrolled cell proliferation in lung tissue, and disruption of signaling pathways in those tissues can confer a normal cell with malignant properties,” Dr. Cho explained.  “Deregulation of only a small set of pathways can confer a normal cell with malignant properties, and these pathways are regulated in response to nutrient availability and, consequently, cell proliferation and growth.

“Phosphate is an essential nutrient to living organisms, and can activate some signals,” he added.  “This study demonstrates that high intake of inorganic phosphates may strongly stimulate lung cancer development by altering those (signaling) pathways.”

In the study, lung cancer-model mice were studied for four weeks and were randomly assigned to receive a diet of either 0.5 or 1.0 percent phosphate, a range roughly equivalent to modern human diets.  At the end of the four-week period, the lung tissue was analyzed to determine the effects of the inorganic phosphates on tumors.

“Our results clearly demonstrated that the diet higher in inorganic phosphates caused an increase in the size of the tumors and stimulated growth of the tumors,” Dr. Cho said.

Dr. Cho noted that while a moderate level of phosphate plays an essential role in living organisms, the rapidly increasing use of phosphates as a food additive has resulted in significantly higher levels in average daily diets.  Phosphates are added to many food products to increase water retention and improve food texture.

“In the 1990s, phosphorous-containing food additives contributed an estimated 470 mg per day to the average daily adult diet,” he said.  “However, phosphates are currently being added much more frequently to a large number of processed foods, including meats, cheeses, beverages, and bakery products.  As a result, depending on individual food choices, phosphorous intake could be increased by as much as 1000 mg per day.”

“Although the 0.5 percent was defined as close to ‘normal,’ the average diet today is actually closer to the one percent diet and may actually exceed it,” Dr. Cho noted.  “Therefore, the 0.5 percent intake level is actually a reduced phosphate diet by today’s scale.”

Dr. Cho said future studies will help refine what constitutes a “safe” level of dietary inorganic phosphate, with recommendations that will be easily achievable in the average population.

“The results of this study suggest that dietary regulation of inorganic phosphates has a place in lung cancer treatment, and our eventual goal is to collect sufficient information to accurately assess the risk of these phosphates,” he said.

John Heffner, M.D., past president of the ATS, stated that this line of investigation in animals addresses the complex interactions between host factors and the environment that underlie cancer in man.  “We know that only some patients who smoke develop lung cancer but the reasons for this varying risk are unknown.  This study now provides a rationale for funding case-control studies in humans to determine the potential role of dietary phosphates in promoting cancer.”

Shredded extracellular matrix (ECM) is toxic to neurons. Chen et al. Reveal a new mechanism for how ECM demolition causes brain damage. The study will appear in the December 29, 2008 issue of The Journal of Cell Biology (www.jcb.org).

A stroke or head injury kills large numbers of neurons through a process called excitotoxicity. A surge of the neurotransmitter glutamate jolts receptors such as the kainate receptor and stimulates cell death. Enzymes add to the death toll by chopping up ECM near the injury site. How ECM breakdown takes out neurons was mysterious. The standard view was that neurons perished because they got separated from the ECM as it dissolved.

Chen et al. Found otherwise when they engineered mice to lack the ECM component laminin in the hippocampus, a brain region often damaged by stroke or injury. If cells languished after parting from the ECM, the researchers reasoned that mice missing laminin would suffer more damage from excitotoxicity. But when excitotoxicity was spurred with an injection of kainate—a molecule that, like glutamate, activates the kainate receptor—the laminin-lacking mice showed less brain damage. After a dose of diced laminin, however, the mutant mice were vulnerable to kainate, indicating that the fragments are the culprit in cell death.

The researchers discovered that chopped-up ECM kills cells by ramping up production of one subunit of the kainate receptor, known as KA1. They speculate that hiking the amount of KA1 subunits might make the receptor more sensitive and thus more likely to trigger an overreaction by the cell.

Although drugs that obstruct the glutamate receptor slow brain cell death, they can lead to serious cognitive impairment and even coma. The study suggests that drugs that block KA1 might provide an alternative way to save brain cells after stroke or head trauma.