Mouse Gene Turned on by Fatty Food Linked to Human Heart-Disease Gene

Date: March 6, 2005

Bar Harbor, Maine - More evidence linking a high-fat diet to heart disease: An international research team has identified a gene that interacts with environmental factors such as diet to influence atherosclerosis susceptibility.

Atherosclerosis - the hardening of the arteries through deposition of cholesterol in the arterial wall - is the disease basis for coronary heart disease, the leading cause of death in the Western world.

As reported in Nature Genetics, the team, jointly led by Dr. Xiaosong Wang of The Jackson Laboratory and Dr. Jacob Lagercranz of Sweden's Karolinska Institute, has identified that Ox40l is a gene that makes C57BL/6J mice susceptible to high-fat diet-induced atherosclerosis. "Thirty percent of the calories in our mouse diet were fat-based - the American Heart AssociationÍs recommended limit," explained Dr. Wang. "Unfortunately, the average American's fat calorie intake exceeds this limit."

Variations of the OX40L gene in humans were found to be associated with the risk of myocardial infarction and coronary artery disease.

Almost two decades ago, Jackson Laboratory Senior Staff Scientist Beverly Paigen, Ph.D., led the team that mapped Ath1 - the first atherosclerosis susceptibility trait in mice. The Ath1 region has since been narrowed to 11 known genes including Ox40l.

Based in Dr. Paigen's laboratory, the research team has now shown that mice with the Ox40l gene "knocked out" have significantly smaller atherosclerotic lesions than control mice, while significantly larger lesions are found in mice over-expressing Ox40l. In clinical studies conducted at the Karolinska Institute, variations of OX40L were found to be significantly more frequent in patients with myocardial infarction than in controls.

"We've identified a novel pathway in atherosclerosis, the leading cause of death in the United States and other industrialized nations," said Dr. Wang. "We've proven that a human disease gene can be found from a causal gene identified in mice. This mouse-to-human strategy is very cost-effective in identifying human disease genes."

The study was funded largely by AstraZeneca.

Finding a human disease gene can cost tens of millions of dollars while identifying a disease gene in mice is comparatively inexpensive, time efficient, and allows a much broader experimental approach. A single gene can be more easily identified in mice and then used to help locate the corresponding gene in humans.

"Collaboration between mouse and human geneticists is so powerful," remarked Dr. Paigen. "Our findings have opened the door for the identification of more atherosclerosis-related genes in mice and unlocked the potential to investigate their human counterparts. We're so excited that our discoveries will benefit the ongoing research efforts of others, and allow them to explore new treatments for heart disease through advances in therapeutics."

The nonprofit, 75-year-old Jackson Laboratory is the world's largest mammalian genetics research institution. Its research staff of more than 465 investigates the genetic basis of cancers, heart disease, osteoporosis, Alzheimer's disease, glaucoma, diabetes, and many other human diseases and disorders. The Laboratory is also the worldÍs source of more than 2,800 strains of genetically defined mice, including mouse models of cardiovascular disease, and is home of the Mouse Genome Database and other essential information resources, as well as an international hub for the training and education of genetics researchers.

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Wang X, Ria M, Kelmenson PM, Eriksson P, Higgins DC, SamnegÎrd A, Petros C, Rollins J, Bennet AM, Wiman B, de Faire U, Wennberg C, Olsson PG, Ishii N, Sugamura K, Hamsten A, Forsman-Semb K, Lagercrantz J, Paigen B. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics advance online publication, March 6, 2005 (doi:10.1038/ng1524).

Contact(s):

Jade Harmer, The Jackson Laboratory, 207-288-6051, jade@jax.org

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