Weight loss after gastric bypass surgery varies widely, and scientists say they have identified a genetic variation that may help explain the discrepancy.
The discovery, detailed in a study published May 2 in the American Journal of Human Genetics, is already driving creation of a gene test that may one day help patients predict how many pounds they might shed after weight-loss surgery.
Some patients lose 60 percent of their weight after the surgery, and others just 15 percent. Factors such as age, activity level and whether a patient has other health problems, such as diabetes, help doctors estimate a patient's potential results.
But sometimes, patients who seem like great candidates for the surgery don't slim down as much as they'd hoped.
"This is heartbreaking for those folks who have been brave enough and struggled enough to get to the point of having surgery and then experience failure in terms of weight loss," said Molly Bray, a professor of epidemiology at the University of Alabama at Birmingham, who was not involved in the research.
"Identifying markers that can predict response to surgery prior to its undertaking would be extremely important," said Bray, whose research involves the genetic basis of obesity.
For the new study, researchers surveyed the genomes of more than 1,000 patients who had Roux-en-Y gastric bypass surgery, where surgeons seal off the upper portion of the stomach to make a smaller pouch and then connect that to the middle portion of the small intestine.
One location turned out to be significantly associated with weight loss after surgery. The location in question doesn't lie within a gene. Genes contain instructions that tell the body to make specific proteins. Instead, it seems to sit in a stretch of DNA between two genes on chromosome 15. The researchers said they're not sure how differences in DNA in that region might influence weight loss, but it may control the adjacent genes, which seem to play a role.
Looking at the different variants at this location, the researchers found that people with two copies of the more common variant lost an average of 39 percent of their starting weight, while the one person in the study who had two copies of the less common variant shed 29 percent of starting weight.
Patients with just a single copy of the less common DNA variant were 2.5 times more likely to lose less than 30 percent of their total bodyweight after surgery than patients without that variant.
Next, researchers checked the activity of the two genes closest to the location of the gene variant.
People with greater expression of the gene closest to the variant in their abdominal fat lost more weight after surgery than those with less gene activity there. That remained true even after researchers adjusted their results for factors such as age, sex, diabetes and body-mass index (a measure of body fat based on a person's ratio of height and weight) before surgery.
To check their results another way, they also looked at the activity of two genes closest to the variant in obese mice given either a gastric bypass or sham surgery. Ten months after the procedures, the gene expression in mice that had gastric bypass was different than in mice that had sham surgeries.
"There's an enormous amount of biology that's changed in response to the surgery," said Dr. Lee Kaplan, director of the Obesity, Metabolism, & Nutrition Institute at Massachusetts General Hospital, in Boston.
Doctors once thought patients lost weight after gastric bypass simply because their stomachs were smaller, allowing them to feel full after eating a lot less.
But recent studies have shown the surgery also alters hormones, gut microbes and the activity of genes.
"That's probably why surgery is so effective clinically, because it does so much," Kaplan said.
Kaplan's team is developing a test to look for patterns in gene activity that he says will be available within a year. It will take a few years beyond that to validate the test and secure U.S. Food and Drug Administration approval, he added.
Such a test could help patients who are on the fence about having the weight-loss procedure, he said. Gastric bypass can be very beneficial for severely obese people, but also carries some risk, especially for those with other significant health problems.
Further studies are needed to clarify the role of the genetic variation identified in the study and, because most of this study's participants were of European descent, to look for other variants that might apply to different ethnic groups.
Kaplan said he also wants to see if they might get the same results with other kinds of weight-loss procedures.
"Genetics makes a contribution to weight loss after surgery. This has put the wind in our sails so now we can go after other questions," he said.