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DIR Papers of the Month

By Jerry Phelps
July 2006

Gene Polymorphism Associated with Coronary Heart Disease Risk

Scientists in the Laboratory of Respiratory Biology at NIEHS discovered a polymorphism for the gene coding for the enzyme soluble epoxide hydrolase that is associated with an increased risk of heart disease in Caucasians. These findings suggest that the gene, EPHX2 may be a cardiovascular disease susceptibility gene. Darryl Zeldin and colleagues at NIEHS along with NIEHS grantee Bruce Hammock at the University of California Davis and other researchers at UNC and Baylor published these findings in the May 15 edition of Human Molecular Genetics.

Ten polymorphisms for EPHX2 have been found to date. The research team analyzed the DNA of 2,065 participants in The Atherosclerosis Risk in Communities Study (ARIC). In Caucasian subjects, one polymorphism, K55R, was significantly more common among people with coronary heart disease than in healthy adults. No significant associations were observed between the polymorphism and coronary heart disease in African-Americans.

Soluble epoxide hydrolase is found in the smooth muscle tissue of the veins and arteries. It regulates endothelial cell function and metabolizes a group of compounds known as epoxyeicosatrienoic acids (EETs). EETs are known to have anti-inflammatory effects and to be potent vascular dilators.

The ARIC, which began in 1987, is a prospective epidemiologic study conducted in four U.S. communities, and is designed to investigate atherosclerosis and variations in cardiovascular risk factors, medical care and disease by race, gender, location, and date. The four communities are Jackson, MS; Forsyth County, NC; suburban Minneapolis, MN; and Washington County, MD.

Citation: 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.

Calpain 11 Gene is Expressed in the Mouse Testis

Mitch Eddy in the Laboratory of Reproductive and Developmental Toxicology and colleagues at Tel-Aviv University cloned the gene for a calcium-dependent thiol protease known as calpain 11 and determined that its expression is specific to the testis. The team also determined that the gene is located on chromosome 17 in mice. These discoveries were reported in the June edition of the journal Molecular Reproduction and Development. Calpains are a family of proteases involved in the intracellular processing of proteins.

The findings that calpain 11 is expressed during spermatogenesis and is located in sperm cells suggest that it is integral to the regulation of calcium dependent signal transduction events during meiosis, and the proper functioning of sperm cells.

Citation: Ben-Aharon I, Brown PR, Shalgi R, Eddy EM. Calpain 11 is unique to mouse spermatogenic cells. Mol Reprod Dev. 2006 Jun;73(6):767-73.

Residential Radon Exposure and Lung Cancer Risk

An epidemiologic study conducted in Connecticut, Utah and southern Idaho did not detect an increased risk of lung cancer associated with residential radon exposure at the low levels of exposure found in study homes.

Studies of uranium miners have consistently shown that radon is a significant risk factor for lung cancer.

Results of individual studies of residential exposure have been inconsistent, but collectively such studies find a small risk associated with radon exposure that is consistent with what would be predicted based on extrapolation from studies of miners.

The current study examined 1,474 lung cancer cases in people 40-79 years of age. Residential histories and data on known lung cancer risk factors were compiled for both cancer cases and the control group, which consisted of over 1,800 people. Radon was measured in current and past residences. Levels were lower than expected; however, the levels in Utah and southern Idaho were about twice that of Connecticut homes.

The authors conclude that "overall, there was little association between time-weighted average radon exposures 5-25 years prior to diagnosis/interview and lung cancer risk." Results from this study were combined with those from other North American studies of residential exposure and together results do show that residential radon exposure increases lung cancer risk.

Citation: Sandler DP, Weinberg CR, Shore DL, Archer VE, Stone MB, Lyon JL, Rothney-Kozlak L, Shepherd M, Stolwijk JA. Indoor radon and lung cancer risk in Connecticut and Utah. J Toxicol Environ Health A. 2006 Apr;69(7):633-54.

Krewski D, Lubin JH, Zielinski JM, Alavanja M, Catalan V, Field W, Klotz JB, Letourneau EG, Lynch CF, Lyon JL, Sandler DP, Schoenberg JB, Steck DJ, Stolwijk JA, Weinberg CR, Wilcox HB. A combined analysis of North American case-control studies of residential radon and lung cancer. J Tox Env Health Part A 2006;69:533-597.

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