NIEHS researchers link gene variation to coronary heart disease

New research at the National Institute of Environmental Health Sciences, part of the National Institutes of Health, found that a common genetic variation makes some people more susceptible to coronary heart disease (CHD). Caucasians who carry this gene variation are approximately 1.5 times more likely to have a CHD event, such as a heart attack, than those who do not have the gene variation. Gene variations are also known as polymorphisms. About 15 percent of all Caucasians have this particular polymorphism.

"We found that Caucasians who carry this polymorphism, named K55R, were at significantly higher risk of coronary heart disease, independent of other risk factors, like cigarette smoking, diabetes, and hypertension. We did not observe the same association in African Americans who had the K55R polymorphism," said Craig Lee, Pharm.D., a researcher at NIEHS and lead author on the study. The study is published in the Volume 15, No. 10 issue of Human Molecular Genetics.

This research showed that Caucasians with the K55R polymorphism had an accelerated break down of beneficial fatty acids called epoxyeicosatrienoic acids or EETs, which are known to play a protective role in the cardiovascular system. These fatty acids help to lower blood pressure, prevent blood clotting and fight inflammation.

The K55R polymorphism is a naturally-occurring, inherited variation of EPHX2--the epoxide hydrolase gene. EPHX2 generates an enzyme that rids the body of beneficial EET fatty acids, as part of normal human metabolism. In people with the K55R polymorphism, this normal process is accelerated and even more of the protective EETs are lost.

"This research builds on a body of evidence suggesting the importance of this gene and its fatty acid products in the cardiovascular system," said David A. Schwartz, M.D., NIEHS Director. "It also suggests that this metabolic pathway may serve as a useful target for the prevention or treatment of cardiovascular disease."

"Improved knowledge about the role this gene plays in the onset of cardiovascular disease makes it possible identify people who may be at greater risk, and also to identify individuals who may be more responsive to new drugs that target the enzymes of this metabolic pathway," said Dr. Darryl C. Zeldin, M.D., a Senior Investigator at NIEHS, who is also an author on the study. "We've been studying this pathway in cells and mice for more than a decade, but this study provides the first direct evidence about its importance to coronary heart disease events in humans."

Coronary heart disease is a major public health problem, with approximately 1.2 million Americans estimated to experience a CHD event this year. Researchers report some preliminary findings showing that people who smoked and carried K55R gene variation were at the highest risk for CHD.

The researchers genotyped 2065 participants for ten known polymorphisms in the EPHX2 gene. The researchers were also able to confirm that there was an increased level of enzyme activity in individuals who had the K55R polymorphism.

"By looking at ten different polymorphisms, we were able to survey the gene and determine that this one particular variation is related to cardiovascular disease risk in Caucasians," said Lee. "More research is needed to determine if this finding is applicable to other populations."

Participants of this study were part of a larger study, the Atherosclerosis Risk in Communities (ARIC) Study, which is funded by the National Heart, Lung , and Blood Institute. The ARIC Study is a long-term study consisting of nearly 16,000 men and women age 45-64 from four diverse communities, including Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD. The study, which started in 1987, seeks to investigate and identify cardiovascular disease risk factors in men and women.

"This study exemplifies the importance of translating basic research findings in the laboratory to clinical studies in humans" said Schwartz.

The National Institute of Environmental Health Sciences (NIEHS), a component of the National Institutes of Health, supports research to understand the effects of the environment on human health. For more information on environmental health topics, please visit our website at http://www.niehs.nih.gov/.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Reference: Lee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW, Hammock BD, Couper DJ, Heiss G, Zeldin DC. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet. 2006 May 15;15(10):1640-9. Epub 2006 Apr 4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16595607&query_hl=1&itool=pubmed_docsum

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