Gene Variants Linked To Metabolic Syndrome And HDL Cholesterol Levels

People with metabolic syndrome have at least three of the following symptoms: abdominal obesity, high blood triglyceride levels, lower good cholesterol (HDL), elevated blood pressure and elevated fasting blood glucose. They are four times as likely to develop heart disease and at least seven times more likely to develop diabetes as individuals without metabolic syndrome.

The investigators, who report their findings in the June issue of the journal Human Molecular Genetics, looked for changes in the CD36 gene, which is located in a region of chromosome 7 that has been linked to metabolic syndrome in several genome-wide studies.

The researchers say linking changes in the CD36 gene to the risk for metabolic syndrome and abnormal levels of good cholesterol is important because as more people in the United States become obese, they also become susceptible to these problems. Better understanding of the relationships between obesity, the gene and disease risk may allow for earlier identification of individuals who are more susceptible to develop metabolic syndrome. Treatments such as medication or lifestyle changes could begin earlier, perhaps preventing or delaying future problems with diabetes or heart disease.

Senior investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research, first identified the CD36 protein in studies with mice. Her research has demonstrated that the protein facilitates the use of fatty acids for energy. CD36 is located on the surface of cells and distributed throughout many tissues, including fat cells, the digestive tract, heart and skeletal muscle.

The investigators — who included M. Alan Permutt, M.D., professor of medicine and of cell biology and physiology; Rosalind J. Neuman, Ph.D., professor of mathematics in psychiatry; and Samuel Klein, M.D., the Danforth Professor of Medicine and Nutritional Science and director of the Center for Human Nutrition — focused on 36 small genetic variations, called single nucleotide polymorphisms (SNPs), in the CD36 gene. A SNP involves a single base-pair change in the DNA.

The team evaluated DNA taken from more than 2,000 African-Americans because variations in the gene are more common in individuals of African and Asian descent than in other racial groups. The researchers expect, however, that these findings also will be applicable in other populations.

"The idea was to look at the different variations in the gene and see whether they were more prevalent in people who also had elevated cholesterol, abnormal blood glucose or the other components of the metabolic syndrome," says first author Latisha Love-Gregory, Ph.D., research instructor in the Division of Geriatrics and Nutritional Science.

Love-Gregory says the research team demonstrated an association between SNPs in the gene and metabolic syndrome.

"There is additional work to do to determine if the function of these genetic variants actually contributes to the development of type 2 diabetes or heart disease," she explains. "We do expect that a number of different changes, in both CD36 and other genes, will be related to these diseases. What we'd like to learn, however, is whether the changes identified in the gene alter the CD36 protein in ways that change its function to make a person more vulnerable."

The team determined that five of the SNPs they examined are more common in people who have symptoms of metabolic syndrome, but a sixth seemed to have a more favorable metabolic effect. The "protective" SNP makes people produce lower amounts of CD36 protein.

Humans have two copies of each chromosome. In this study, people who had the protective variant on only one of their copies of chromosome 7 were less susceptible to metabolic syndrome. But people with two copies of the variant, who were completely deficient in the CD36 protein, did not appear to be protected. They tended to have lower levels of HDL, the so-called good cholesterol.

"A bit less CD36 protein may improve your risk profile, but people need some CD36 function," Abumrad says. "It's like requiring a certain level of fat in the diet. Fatty acids are important for optimal function of many tissues — from pancreatic beta cells to skeletal muscle to the heart — but too much fat creates a problem."

Love-Gregory and Abumrad found that many variants influenced blood levels of HDL cholesterol. Now they are taking a closer look at the relationship between CD36 and HDL cholesterol. Higher levels of HDL normally are considered positive, but because changes in the CD36 gene seem to influence HDL, the researchers want to make sure that the HDL molecule isn't being altered in composition or function.

"We're going to follow up on the HDL component of the study," Love-Gregory says. "We're also going to look for additional variants in the promoter region of the gene that controls how the gene is regulated. And we're planning to look for evidence of these gene variants and their associations with HDL and the metabolic syndrome in other populations and ethnic groups."

This research was supported by the National Institutes of Health.