In a 10-year, NIA-funded collaboration, U.S. and Italian investigators are conducting genetic research on the scenic Mediterranean island of Sardinia.
One autumn day in 1995, Giuseppe Pilia, M.D., Ph.D.*, then a post-doctoral fellow in the research laboratory of David Schlessinger, Ph.D., stopped by Dr. Schlessinger’s office in Baltimore with an intriguing idea. Schlessinger, senior investigator and head of the National Institute on Aging’s (NIA’s) Laboratory of Genetics , listened as Pilia pitched his proposal. Before the session ended, Dr. Schlessinger realized that Pilia’s idea could have a significant impact on aging research.
Pilia outlined why the picturesque Mediterranean island of Sardinia—Pilia’s native soil, located about 120 miles west of the Italian peninsula—offers a rare opportunity to accelerate the pace of aging-related genetic investigation. Schlessinger agreed and promoted the premise within the NIA leadership and review system. Planning soon began on what would become a $22 million, 10-year population study funded by NIA.
Dubbed the SardiNIA Project , the study is a joint effort by NIA; the Institute of Neurogenetics and Neuropharmacology of the Italian Research Council, led by Professor Antonio Cao; and statistical genetic analysts working under Goncalo Abecasis, D.Phil., at the University of Michigan, Ann Arbor. A team of Sardinian scientists originally organized by Dr. Pilia, is performing research work on the island under the direction of Manuela Uda, Ph.D.
SardiNIA’s goal is to identify gene variants (alleles) that affect the occurrence of certain traits such as obesity, depression, or high blood pressure, which may increase the risk of certain diseases in later life, such as heart disease, diabetes, and dementia. Observable traits resulting from the interaction of genetic and environmental factors are called phenotypes.
The SardiNIA scientists analyze selected alleles at the molecular level, mapping and comparing their basic building blocks or nucleotides. They look for SNPs—single nucleotide polymorphisms—which are places in the DNA where either of several nucleotides can be present in different individuals (in other words, “variants” occur at those locations).
Schlessinger explains: “Across the general population, multiple alleles may occur for the same gene. A single allele that occurs for a gene may or may not affect the function of the gene. For example, one type of allele may be associated more with higher cholesterol levels than another allele is. Finding such associations and then describing how they affect a gene’s function move us a step closer to finding methods of disease prevention and cure.”
Most countries have a heterogeneous population. In genetics, that means the inhabitants come from multiple gene pools, reflecting generations of intermixing by people of different lineages. The lineage of most Sardinians goes back approximately 8,000 years to the island’s original settlers. Sardinians are what is known as a “founder population.” Their relative genetic homogeneity, or similarity, simplifies population genetic analyses. The relatively large population (about 1.5 million people) also offers important statistical advantages.
“The SardiNIA study provides researchers with an efficient and cost-effective resource for identifying genetic risk factors for traits of interest,” says NIA Director Richard Hodes, M.D. “Combined with recent advances in the technology of genetic analysis, SardiNIA is one of the most intriguing population genetic studies now underway in aging-related research.”
In the initial 5-year phase of the study, scientists captured crucial baseline data on 98 traits of interest from more than 6,100 participants. A partial list of these traits includes age, body mass index, hip circumference, weight, cholesterol level, blood pressure, depressive symptoms, and levels of anxiety.
The second 5-year phase tracks the SNPs in participants to determine alleles associated with certain phenotypes, and to begin to test whether those alleles and/or their interactions with environmental factors predict, for example, higher levels of cholesterol. The researchers continue to find and analyze more alleles that appear associated with age-related traits and to confirm these associations in other large-population studies. Researchers also are on the alert for environmental factors that could alter the effects of the genes.
New genotyping technology has accelerated this work. SNP mapping arrays are membranes or glass slides—sometimes called gene chips—that are layered with hundreds of thousands of SNP variants. The arrays allow scientists to make efficient, highly detailed analyses of millions of SNPs in the DNA of a single individual, and then to compare them with SNPs in the DNA of other individuals. SNP mapping arrays are an example of “high-throughput” technology, which facilitates rapid, large-scale analyses of many samples to yield large amounts of data.
Using this new technology, SardiNIA scientists can tag many SNPs that appear to correlate with the values of traits of interest. Once scientists identify these SNPs, they can look for ways to activate the gene to perform its function or deactivate the gene to prevent it from doing so, whichever is desirable.
One important and challenging task in this and other studies of complex genetics is the organization and analysis of the genetic data. Abecasis and his statistical genetics team have developed new computational tools and analytical methods that expedite this work.
Several initial findings provide tantalizing examples of what may come. For example, scientists have identified alleles that appear to affect fasting glucose levels and the tendency toward obesity (PLoS Genetics, Vol. 3, No. 7 ). High glucose levels and obesity are known risk factors in several diseases. Approaching the problem from the genetic side, scientists are looking for ways to block or enhance the effects of the alleles. People who learn they have the associated alleles can work to control the environmental factors that increase or decrease their risks.
Recently, Schlessinger and colleagues reported the identification and molecular analysis of a gene associated with uric acid levels in blood—a significant finding because high uric acid levels can lead to gout and increase the risk of cardiovascular and kidney disease (PLoS Genetics, Vol. 3, No. 11 ).
An even more recent journal article , published January 13, 2008, presented data from the SardiNIA, Finland-US Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION ), and Diabetes Genetics Initiative (DGI ) studies. It reported the discovery of seven new genetic variants associated with changes in lipid levels in the body, and confirmed this association in 11 other genetic variants. Lipids are natural substances, such as fats and cholesterol, that are involved in energy storage. The researchers found that genetic variants associated with increased low-density (or “bad”) cholesterol are more common among people with coronary artery disease (CAD). Finding these genetic variants opens the door to possible improvements in the diagnosis, prevention, and treatment of CAD, a leading cause of death in U.S. men and women.
Scientists will continue to mine and assay the genetic information from the SardiNIA project. “We’ve completed just the first pass at what promises to be a very rich source of new scientific insights,” says Schlessinger. “In the years to come, we’re expecting to find additional associated genes and to help catalyze the study of their function and possible interventions in disease.”
“This project owes a great deal to Dr. Pilia,” he adds. “He planted the seeds of the project that are now producing abundant fruit.”
*Tragically, Giuseppe Pilia, M.D., Ph.D., passed away in 2005. The team he organized continues to work together, fortified by his inspiration.