$1.7 million grant to advance understanding of genetic influences on diabetes

Scientists at Southwest Foundation for Biomedical Research (SFBR) expect to make big leaps in their understanding of genetic influences on diabetes, thanks to a new $1.7 million grant awarded to Dr. Joanne Curran, the grant's principal investigator.

The grant from the National Institute for Diabetes and Digestive and Kidney Diseases will allow Dr. Curran and her colleagues to conduct a more detailed investigation on 100 genes that previous SFBR studies have shown to play a role in various risk factors for diabetes and other metabolic diseases. She will now look closely at DNA variations within the genes themselves to see how those changes affect the genes' output, and ultimately, how these genes exert their influence on such things as blood glucose and insulin levels and body fat.

“We're looking for functional changes within the DNA sequence of these particular genes that are causing certain individuals to have these risk factors for diabetes,” Curran said. “Our previous work has uncovered genes that are influencing fasting glucose levels, body mass index, and other health traits related to diabetes risk. So now we want to find out how these genes vary among individuals and which DNA variations within the genes themselves impact their function and their resulting influence on human health.

“Then maybe we can find a way to target a particular gene and manipulate its function so that it doesn't result in high blood glucose levels, for example.”

The need for new methods of preventing and treating diabetes is critical, as rates of type 2 diabetes, often called adult-onset diabetes, continue to climb in the United States and other first-world countries, particularly as obesity rates have reached epidemic levels. It disproportionately affects the growing Hispanic population, where the prevalence of type 2 diabetes is two to three times higher than in non-Hispanic whites. Obesity often precedes the onset of type 2 diabetes, which can make people more susceptible to a host of other health problems, including cardiovascular disease, kidney disease, and blindness. Type 2 diabetes accounts for more than 90 percent of diabetes worldwide, with scientists estimating that there will be 220 million cases worldwide by 2010.

“Right now, the best prevention we have for diabetes is lifestyle change,” said Curran. “But what if you have a genetic predisposition that's causing your high levels of blood glucose? Then lifestyle changes alone may not help you. That's why we need to find the genes involved and the DNA variations that affect those genes' function. That will give pharmaceutical companies the information they need to develop new medications to fight this growing health problem.”

The hunt for diabetes genes

SFBR geneticists have particular expertise in the search for genes that influence common complex diseases like diabetes and other disorders that are influenced by numerous environmental and genetic risk factors. In September of 2007, they announced a new research method they devised to speed up this cumbersome hunt.

That study, led by SFBR geneticist Dr. John Blangero, and detailed in the scientific journal Nature Genetics, utilized genetic material from blood samples from 1,240 participants in SFBR's ongoing San Antonio Family Heart Study. The San Antonio Family Heart Study includes approximately 1,400 members of 40 Mexican-American families in the San Antonio area, who are participating in a long-term investigation of the genetic determinants of heart disease, diabetes and obesity.

Instead of trying to sift through all 25,000 genes in the human genome, the researchers used transcriptional profiles – measures of the output of a person's genes – to identify genes that are self-regulated, or cis-regulated, meaning they harbor variations that affect their own output. That enabled them to rapidly narrow in on genes that likely have a causal effect on a particular disease or disease trait. In the Nature Genetics paper, the SFBR team described how it discovered the VNN1 gene's influence on the level of HDL, or “good cholesterol,” by statistically correlating the gene expression profiles with the variable HDL cholesterol levels in the San Antonio Family Heart Study participants.

SFBR scientists have used that same approach to find genes associated with other diseases, including 203 genes that correlate with risk factors for diabetes. From that list of 203 genes, Dr. Curran has selected the top 100 for further examination. She will look at the 100 genes that showed the strongest evidence of being self-regulated and the strongest correlations with diabetes risk factors such as a high level of glucose in the blood after a period of fasting, known as fasting glucose; other risks determined by tests of glucose and insulin; and a high level of fat as determined by assessment of the body mass index, the measure of fat in relation to height and weight.

What makes these genes tick?

In her more detailed investigation, Curran's group will utilize genetic samples from 182 founder individuals in the San Antonio Family Heart Study and search for variations in an area of the genes known as the promoter region, a key regulatory region of the gene. “By focusing on the promoter region, we're likely to find functional DNA variants within the genes, or variants that truly have a functional consequence in the cellular system, which is our ultimate aim,” said Curran.

She further explained, “Analyzing the founders [of the San Antonio Family Heart Study] enables us to capture most of the genetic variation that's present in the population without having to sequence everybody. These are the people who contribute most of the genetic information to the family trees in our study. So by picking those individuals, we really increase our chance of getting all the genetic information we need.”

Impact on human health

Curran sees a two-fold benefit from identifying genes that influence our risk for diabetes. “Knowing you have a genetic predisposition for diabetes can be a wake-up call that you need to stay in shape and manage your diet to try and keep your blood sugar under control,” she said. “But in cases where a person still exhibits those risk factors, despite lifestyle changes, perhaps a drug targeting genes that influence the risk factors can keep them under control.”

The researchers also will test the findings of this study with two independent populations. One is in Wisconsin, the Metabolic Risk Complications of Obesity Genes Study, directed by Dr. Ahmed Kissebah, of the Medical College of Wisconsin, a co-investigator on Curran's study. The other is a group involved in the San Antonio Family Gall Bladder Study, directed by SFBR geneticist Dr. Ravindranath Duggirala, a consultant on Curran's study.

Other co-investigators on Curran's study include Drs. John Blangero and Jac Charlesworth.

Southwest Foundation for Biomedical Research is one of the leading independent biomedical research institutions in the United States, dedicated to advancing human health through innovative biomedical research. It is recognized within scientific and academic communities worldwide for the quality of its basic research into the nature, causes, preventions, and treatments for disease. SFBR's staff of more than 75 doctoral-level scientists conducts nearly 200 major research projects, with marked success in the areas of genetics, neonatal development, metabolic disorders and infectious diseases.