Researchers Find Gene Associated with "Good Cholesterol"

Using a powerful new approach termed a "gold mine of gene discovery," a team of multi-institutional researchers have identified a novel gene (VNN1) that appears to play a significant role in determining blood levels of the so-called "good" cholesterol also known as HDL-cholesterol (HDL-C). Low levels of HDL-C are associated with increased risk of cardiovascular disease, whereas high levels are thought to be protective.

The study results were presented October 25, 2007, at the American Society of Human Genetics, by Joan Curran, PhD, assistant scientist with the Southwest Foundation for Biomedical Research (SFBR), San Antonio, Texas. Collaborating researchers are from the Medical College of Wisconsin, in Milwaukee, and ChemGenex Pharmaceuticals based in Australia. The new technology is described in the September, 2007, issue of Nature Genetics.

The researchers have also identified five genes associated with VNN1 that may constitute members of a biochemical pathway related to cholesterol metabolism. Studying this possible pathway might prove useful in identifying new targets for treatment interventions to reduce cardiovascular risk.

The discovery also has implications for obesity and obesity-related health complications, known as the metabolic syndrome, a phrase coined in the early 1980s by Ahmed Kissebah, MD, PhD, Professor of Medicine and Pediatrics and Director of the TOPS Center for Obesity and Metabolic Research at the Medical College of Wisconsin. Dr. Kissebah practices at the Froedtert & Medical College Endocrinology, Metabolism and Clinical Nutrition Clinic.

According to Dr. Kissebah, one of the authors of the research report, reduced level of the good cholesterol HDL is one of the main hallmarks of metabolic syndrome, a term which is now recognized worldwide. This is a cluster of features commonly associated with upper body obesity with an increased waistline, and is proven to be genetically passed through families.

"Now we can understand why the metabolic syndrome is strongly associated with cardiovascular disease. The good news is that these findings should pave the way for a new generation of treatments that could overcome the health complications of obesity and this syndrome," says Dr. Kissebah.

The researchers used the new technology they developed to rapidly sequence the human genome to find the VNN1 gene. The VNN1 gene and its effects were identified in a large-scale expression of all the mediators that regulate a gene's action from 1,240 individuals enrolled in the San Antonio Family Heart Study. This is a multigenerational study evaluating the risk of heart disease in Mexican-Americans.

Once the VNN1 gene was identified, the researchers pursued a statistical association between the expression of the gene and the concentration of HDL-C levels, which are a determinant of cardiovascular risk.

By sequencing the DNA of the study subjects, the researchers were able to show differences or variances in the coding regions of the gene which instructs its mediators to regulate the formation of its protein that carry out the normal gene-directed body functions as well as any dysfunction that can cause disease.

This association of VNN1 with HDL-C levels serves as proof of principle for an exciting new gene discovery approach that focuses on what are called "cis-regulated" genes. "The ability to pinpoint the cis-regulated genes not only speeds up the discovery process, but means that you immediately have a good target for drugs to treat those diseases that they influence," says Dr. Curran, the first author of the report.

According to Greg Collier, CEO of ChemGenex, "This research method has tremendous potential to accelerate the development of pharmaceutical therapies to target the genetic causes of a whole range of diseases that affect people worldwide."

Each year, Medical College of Wisconsin physicians care for more than 180,000 patients, representing nearly 500,000 patient visits. Medical College physicians practice at Children's Hospital of Wisconsin, Froedtert Memorial Lutheran Hospital, the Milwaukee VA Medical Center, and many other hospitals and clinics in Milwaukee and southeastern Wisconsin.