A Genetic Test for Diabetes Risk

When I was a destitute graduate student several years ago, I decided to earn a quick $75 by signing up for what sounded like a relatively innocuous clinical study. An I.V. in my left arm would feed precise amounts of glucose and insulin into my bloodstream, while from my right arm a nurse would periodically draw blood to test for glucose. The study would assess how effectively my body responded to sugar, a measure that predicts risk for developing type 2 diabetes.

As someone with a family history of the disease, I had long had a shapeless fear of it. A phone call from the nurse a few days later turned that vague anxiety into something much more concrete. The blood tests showed I was “insulin resistant,” meaning that my muscle, fat, and liver cells were not responding to insulin as efficiently as they should–significantly boosting my risk of diabetes.

About 20.8 million people in the United States have diabetes, and another 50 million or more are at risk. Although the onset of the disease can be delayed–sometimes even prevented–with diet and exercise, efforts by doctors and public-health agencies to encourage healthy habits are making marginal progress at best.

In the last several months, however, a potential new tool for diabetes prevention has come to market. A test developed by the Icelandic genomics company deCode Genetics and marketed to consumers by San Francisco-based DNA Direct determines whether people carry copies of a genetic variation that can greatly increase the risk of developing type 2 diabetes. It’s available for $500 through a website, and DNA Direct’s marketing material suggests that positive results will give people extra motivation to get fit. But critics say there is no evidence that this test will succeed where so many public­-health efforts have failed.

Worth It?
Diabetes is the result of a complex mix of genetic and environmental factors. But recent genomic studies have identified several genetic variations that contribute heavily to the disease. The one that exerts by far the biggest influence occurs in a gene called TCF7L2, which was discovered by scientists at deCode in 2005; almost 20 percent of people with type 2 diabetes carry two copies of the high-risk version of the gene. These people are thought to secrete less insulin, a crucial hormone that signals cells to store glucose for energy. A single copy of the varia­tion somewhat increases the risk of contracting the disease, and two copies double the risk, regardless of other risk factors.

The most likely customers for the new test are people with a family histories of the disease, like me, or early warning signs such as high blood sugar, says Ryan Phelan, founder and CEO of DNA Direct. And preliminary evidence suggests that people who already have diabetes might benefit as well: research presented at a conference this year found that people with the high-risk genetic variant are less likely to respond to a class of drugs that includes some of the most commonly prescribed treatments for type 2 diabetes.

But for people who don’t have ­diabetes, doctors’ advice would be the same whether the test came back positive or negative: maintain a healthy weight, and exercise. So what’s the point of testing? “If they know they’re at an increased risk, they will be motivated toward stronger interventions, be it losing weight or quitting smoking,” says Phelan.

Not everyone agrees. David ­Altshuler, a geneticist at Harvard and MIT’s Broad Institute for genomic medicine in Cambridge, MA, and a physician who treats diabetes patients at Massachusetts General Hospital in Boston, was one of the researchers who reported in the New England Journal of Medicine last year that among people considered pre­diabetic–meaning their blood sugar was high but not within the diabetic range–those with the high-risk variant of TCF7L2 were more likely to develop diabetes than those with the normal version. The researchers also found that exercise and diet could slow or prevent onset of the disease, regardless of a person’s genetic status. Yet ­Altshuler says he would not recommend the test to his patients. He says that although it appears to be accurate–the variation has been linked to type 2 diabetes in multiple populations–“there is no evidence that this genetic test does result in an improved health outcome.” Highlighting patients’ other risk factors, such as body mass index, often fails to inspire lifestyle changes, he points out, and it’s not clear that a piece of genetic information will be any different.

Altshuler also worries that the test could have unintended consequences. Someone who turns out to lack the high-risk variation might slip into unhealthy habits, he says. Other critics have suggested that positive results might instill in their bearers a sort of genetic fatalism, giving them an excuse not to diet and exercise because diabetes is already written into their genes.

Given the uncertainty about the test’s impact, Altshuler argues that it’s too soon to market it to consumers. He suggests that, like drugs, genetic diagnostics should undergo clinical trials to prove their effectiveness. “If it turns out that people given this information reduce their risk of diabetes in a cost-effective way, I’m all for it,” he says. “On the other hand, $500 is a lot to spend if no good comes of it.”

But deCode CEO Kári ­Stefánsson, thinks it’s time to make the test available. “Once you have discovered a sequence variant [linked to disease],” he says, “you could make the moral argument that people who want to know have the right to do so.”

Getting Personal
While many genetic tests are already commercially available or in the works, deCode’s is the first to assess risk for a common disease that many people can relatively easily prevent or delay. People with family histories of certain cancers can undergo tests that detect mutations linked to those diseases, but the recommended interventions can be as drastic as preëmptive mastectomy. Scientists have also identified a genetic variant linked to increased risk of Alzheimer’s disease, but in that case, there are no recommended interventions at all.

The deCode diabetes test could be a bellwether for diagnostics that predict risk of heart disease, hypertension, and other problems that can be ameliorated by lifestyle changes. “This test is an example of the direction we’re headed over time,” says Benjamin ­Wilfond, an ethicist who studies genetic testing at the University of Washington School of Medicine in Seattle. “This is potentially the sort of information that would be relevant to everyone.”

But as Altshuler points out, we have little information on whether people really do make lifestyle changes in response to genetic tests. And the few studies that have been done are not encouraging.

People, it seems, don’t want to hear bad news–or they simply ignore it. In one study of smokers, scientists found that those who tested positive for a genetic variant that increased their risk of developing lung cancer were more likely to have forgotten the result six months later than those who tested negative. And preliminary results from a study sponsored by the National Institutes of Health suggest that healthy people aren’t particularly interested in this type of testing. In the study, scientists offer healthy people a prototype test that detects 15 genetic variants implicated in eight common health conditions, including diabetes, heart disease, high blood pressure, and lung cancer–all of which can be prevented or delayed by changes in lifestyle. But so far, only about 10 percent of those approached have chosen to take it. “We think they don’t see themselves as particularly vulnerable,” says Colleen McBride, a scientist at the National Human Genome Research Institute and the study’s leader.

If healthy people got interested in genetic testing, they would probably be the group to benefit most. If they were found to be at high risk, they could try to prevent even the first signs of disease. “Right now, we can’t get on the radar screen of healthy, young individuals because they don’t see themselves as susceptible to diseases that occur later in life,” says McBride. But new genetic tests “might be the kick start they need to engage them in the process,” she says. “The more personal the risk is, the more likely they are to react to it.”

When I first learned about my own risk for diabetes, I began exercising religiously and viewed white flour and sugar with suspicion, with the result that I dropped 30 pounds. Since then, my blood sugar tests have all been normal. As a result, my vigilance waned. That’s why I decided to order the test, which is almost as easy as buying a book from Amazon: a credit card and the time to answer a quick questionnaire about family history and other risk factors are all it takes. I sent in my DNA-coated swabs a few weeks ago and am awaiting my results. I realize that I’ll need to keep exercising and eating right regardless, but I want to know anyway, partly out of curiosity–a positive result could explain my own lengthy family history of diabetes–and partly because I think that for me, a positive result will provide extra motivation. Every little bit counts.

Update: For those of you who are curious, I finally got my test results last week. (Several weeks late, I might add.) I am negative for the high-risk allele. The results bring some relief, but not much. As my personalized report from DNA Direct points out, “Having a negative test result does not guarantee that you will never develop Type 2 diabetes.” I still have other risk factors for the disease.

In fact, the biggest relief had nothing to do with diabetes. Rather, it came from not having to publicly expose a genetic vulnerability. The Genetic Information Non-Discrimination Act, which would prohibit discrimination in employment or insurance on genetic grounds, is still lounging in the Senate, despite presidential support and a whopping margin (420-3) in the House of Representatives.

For me, the most fruitful aspect of getting tested was the reporting that went along with it. It forced me to face anew the seriousness of this disease and my own risk factors, and to talk about this with family and friends. When I told my mother about taking the test, she decided to talk with her own mother about my maternal grandfather and great-grandfather, both of whom died of diabetes-linked complications. The end result: a much more thorough family history than we had before.

If you want to beef up your own family medical history, check out My Family Health Portrait, a website created by the U.S. Department of Health and Human Services to help citizens create and share family health histories.

Emily Singer is the biotechnology and life sciences editor of Technology Review.