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NIA Searches for Genes Involved in Age-Related Diseases

By Doug Dollemore

A 5-year, $5 million international research initiative funded by the National Institute on Aging could help scientists unravel the underlying genetic processes involved in certain age-related traits and diseases.

The ProgeNIA project will focus on Sardinia, an isolated Mediterranean island where historically there has been little immigration. As a result, most inhabitants share common ancestors and have inherited many of the same genetic traits. The interrelatedness of this population should simplify the identification of genes involved in age-related conditions such as cardiovascular disease.

"With this project we want to study aging, and in particular to identify genes involved in the development of several pathophysiological conditions typical of old age," said Dr. David Schlessinger, chief of NIA's Laboratory of Genetics. "The Sardinian population, thanks to its genetic patrimony, can make a fundamental contribution to the understanding of human biology."

Dr. Giuseppe Pilia, director of the ProgeNIA project, in his laboratory. The 5-year study is funded by the National Institute on Aging.

The project, a collaborative effort of NIA and the Italian National Research Council, officially began last November. It will be directed by Dr. Giuseppe Pilia of L'Instituto sulle Talassemie ed Anemie Mediterranee in Cagliari, Sardinia. The investigators aim to recruit more than 4,000 men and women ages 14 and older to participate in the project. In the first phase, volunteers will undergo a series of tests. During these evaluations, investigators will be looking in detail at two traits: high arterial stiffness and positive emotions. Once volunteers who have extreme values for one or both of these two traits have been identified, investigators will seek out family members to determine if they also have these extremes. After that, investigators plan to conduct genetic analysis on individuals who share those traits to try to identify underlying genes.

The traits were selected for several reasons. Independent data from NIA's Baltimore Longitudinal Study of Aging identifies vascular stiffness as perhaps the most important predictor of mortality from heart disease. The ability to reduce vascular stiffness could have a major influence on reducing deaths from heart disease. In addition, it has been reported that positive emotions — joy, happiness, love and excitement — can have profound impact on life satisfaction and health as we age. Both the physical and emotional traits are considered to have strong genetic components and have been extensively studied by NIA scientists.

Sardinia, which was first settled around 6,000 B.C., is home to one of the world's few "founder" populations. These populations, including those located in Iceland, Finland and French-speaking Quebec, arose from small numbers of individuals. Over time, these populations grew in size without much immigration from the outside world. Because most of the society is interrelated, individuals share much of their genetic information, which makes it easier to track genetic effects through generations.

A rugged, isolated island, Sardinia is home to one of the world's few large "founder" populations, settled thousands of years ago by a group that constructed sacred sites, like the tomb area shown here.

The scientists will concentrate their research efforts in Ogliastra, a region on the eastern side of the island surrounded by mountains and the Mediterranean Sea. Because of the terrain, the 300,000 residents of this region have traditionally been isolated from other islanders, making them an ideal founder population. "Sardinians speak of Ogliastra as an island within the island," Schlessinger says.

When a particular genetic trait, such as extreme arterial stiffness, exists in founder populations it is likely that the same one or few genes are responsible for the trait in all affected individuals. Once the genes for a certain complex trait are identified within a founder population, researchers can use this information to isolate interacting genes and assess their importance in more heterogeneous populations, like those of mainland Europe or the United States.

"This study can ultimately help prevent some diseases by letting us know who has the risk factors that indicate they should change diet or exercise or otherwise change their lifestyle in a way that might save lives," Schlessinger said.

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