Clues to Kidney Troubles in Native Americans With Type 2
Robert Hanson, MD, MPH
Investigator, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases
ADA Research Funding
ADA-JDRF Award in Genetics of Diabetic Nephropathy
It may come as a surprise that the highest rates of type 2 diabetes in the world are found in a small, rural community just south of Phoenix. It’s called the Gila River Indian Community, and the people living there are almost all Pima Indians, a tribe whose history goes back thousands of years.
The Pima may not be as well known as the Apache or Navajo, but among diabetes researchers they’re famous: The Pima experience type 2 diabetes at a rate seven times higher than the American average. More than half of all Pima Indians over age 45 have type 2. In 1965, the National Institutes of Health began a long-term study of the Pima, hoping to isolate factors that put them at higher risk.
Over the years, the study—now run by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)—led to discoveries that resonated far beyond the Gila River community. Researchers found that diabetes runs in families and that high blood pressure is a key risk factor for complications of diabetes, such as eye disease (retinopathy) and kidney disease (nephropathy). And because the community is small and closely related, analyzing the DNA of Pima patients has also helped researchers isolate genes that contribute to diabetes and obesity.
Phoenix-based NIDDK researcher Robert Hanson hopes that the long-term nature of the Pima study will help him unravel yet another mystery: Why do some people with diabetes get kidney disease while others don’t?
Kidney disease is a major issue for people with diabetes. The kidneys are the body’s filters. As blood is pumped through tiny blood vessels in the kidneys, specialized cells remove waste and impurities. Diabetes can damage the fine network of blood vessels in the kidneys, making them less efficient or causing them to fail entirely, which can lead to a lifetime of dialysis, the need for a kidney transplant, or death.
According to the National Kidney Foundation, a third of people with type 1 diabetes and up to 40 percent of people with type 2 will suffer kidney disease at some point. “People who develop kidney disease are at high risk for eye disease [and] for going on dialysis, and [they] have an increased risk of mortality,” Hanson says.
With the help of a grant from the American Diabetes Association and the work of Katalin Susztak, MD, PhD, of the University of Pennsylvania, Hanson is using the emerging science of epigenetics to understand who faces the highest risk for kidney disease. Epigenetics looks at how our genetic code—the DNA blueprints we’re born with that tell our cells how to act—is modified over time. “Epigenetic factors are where genes and the environment meet each other,” Hanson says. “These are things that are not necessarily inherited, but things that modify the DNA.”
Like notes added to a set of blueprints after the fact, epigenetic changes affect the DNA’s instructions. When it comes to kidney disease, for example, Hanson thinks years of exposure to the symptoms of diabetes may change the way the body reads its DNA, increasing the risk of kidney disease later in life. “My suspicion is [that] being exposed to high blood sugars or high blood pressure may cause people who have a genetic susceptibility to have kidney disease in the future,” he says.
Once again, the Pima are helping us understand why. Because researchers have been gathering health information and blood samples from the Pima for so long, Hanson is able to search for tiny changes to DNA over time. “We take blood early and see if they develop kidney disease 20 years later,” he explains.\
Specifically, Hanson’s looking for methylation, chemical changes to individual links in the DNA chain. He’s hoping to find consistent patterns: a specific set of changes that always appears in people at high risk, for example. “We were able to look at people before they got kidney disease and see what predicts who goes on to get kidney disease,” he says.
If Hanson could identify a pattern, researchers might be able to head off kidney disease in people with diabetes years, or even decades, before it does damage. “The first thing would be to identify people early and design a diagnostic test to tell if a person was high risk,” he says. “If that’s as far as it went, it would be a big improvement,” allowing doctors to treat vulnerable patients before too much damage is done.
As with so many other discoveries, if a pattern can be found in the Pima, it’s likely the results could help people with diabetes around the world. Says Hanson: “Most of the risk factors in the Pima turn out to be risk factors for other people with diabetes.”
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