ScienceDaily (Apr. 25, 2006) — A rare gene variant in humans helps to protect against two of the country's top killers -- type 2 diabetes and heart disease -- as well as against hypertriglyceridemia, a condition that increases the risk of heart disease, obesity, and pancreatitis. A team of researchers from Harvard School of Public Health (HSPH) and the Channing Laboratory published their findings in this week's issue of the Proceedings of the National Academy of Sciences.

Individuals who had the gene variant had 12 percent lower levels of triglycerides in their blood serum than subjects who did not have the variant. Risk of heart disease was 34 percent lower for those with the variant. Risk for type 2 diabetes was 48 percent lower among obese individuals when compared to other obese individuals who did not have the variant.

"This is a perfect example of the interdisciplinary studies between population sciences, nutrition, and basic scientists at HSPH," said Gökhan Hotamisligil, a senior author and James Stevens Simmons Professor of Genetics and Metabolism. The lead author was HSPH Research Associate Gurol Tuncman.

The gene was first identified in mouse studies as a mediator of metabolic disease. Mice that lack this gene, which encodes for a lipid-binding protein called aP2, were partially resistant to type 2 diabetes and exhibited strong protection against atherosclerosis. The HSPH and Channing team -- representing scientific contributions from five separate research groups -- investigated whether the same held true in humans. They reviewed the medical and genetic records and studied the genetic material of 7,899 participants in the Nurses' Health Study and the Health Professionals Follow-Up Study. Of the group, 4.3 percent had the variant.

The team utilized molecular and cellular techniques in fat cells as well as in human fat tissue samples. They found that the variant T-87C, which sits on the promoter region of the gene that produces the aP2 protein, interferes with the gene and results in less production of aP2 in individuals that carry this variant.

"In other words, this genetic variant in humans looked like a milder version of the mouse knockout model," said Eric Rimm, HSPH Associate Professor of Epidemiology and Nutrition. In the U.S., more than 65 percent of adults and 16 percent of children are overweight. Nearly 24 percent of adults have metabolic syndrome, a constellation of conditions that includes obesity, insulin resistance, and hypertension.

The identification of the T-87C variant indicates that aP2 might play a similar role in humans as it does in mice. The significance of this finding may include a potential target for drugs designed to reduce aP2 levels, offering a possible means to protect against some of the world's most prevalent chronic diseases, say the authors.

This work was supported in part by grants from the Iacocca Foundation, NIH, and American Diabetes Association. Samples used from the Nurses' Health Study and Health Professionals Follow-Up Study were supported by NIH grants. Lead author Gurol Tuncman is a recipient of a postdoctoral fellowship from the Iacocca Foundation to conduct this interdisciplinary project and was supervised by both Rimm and Hotamisligil.

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Adapted from materials provided by Harvard School of Public Health.

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