Genetic Factors May Help Determine Patient's Response To Gastric Bypass
May 3, 2013

Genetic Factors May Influence Gastric Bypass Surgery Success

redOrbit Staff & Wire Reports - Your Universe Online

A DNA sequence variation can help predict the amount of weight loss that a person will experience following gastric bypass surgery, researchers from Massachusetts General Hospital (MGH), Merck Research Laboratories, and the National Institute of Diabetes and Digestive and Kidney Diseases claim in a new study.

The study, which was published Thursday in The American Journal of Human Genetics, discovered that a gene variant found on chromosome 15 can explain why the success of bariatric surgery varies so greatly, and could also help doctors determine which overweight patients would most benefit from the procedure.

According to the researchers, it is the first study to identify genetic predictors of weight loss following gastric bypass, and the results could help lead to the development of new treatment options of obesity and related causes such as diabetes and cardiovascular disease.

“We know now that bypass surgery works not by physically restricting food intake but primarily through physiological effects — altering the regulation of appetite to decrease hunger and enhance satiety and increasing daily energy expenditure,” senior author Lee Kaplan, the director of the MGH Obesity, Metabolism and Nutrition Institute at MGH, said in a statement.

“Genetic factors appear to determine a patient's response to gastric bypass, and the identification of markers that predict postoperative weight loss could provide important insight into those physiological mechanisms,” he added. “The fact that genetics appears to play such an important role in how well bypass surgery works in an individual patient gives us even more evidence that obesity results from dysfunction of the biological mechanisms that regulate fat mass and body weight and not solely from aberrant behavior or limited willpower.”

Kaplan and his colleagues conducted genome-wide association studies of over 1,000 patients who underwent gastric bypass surgery at the Boston-based medical facility between 2000 and 2011. They analyzed nearly two million gene sites for associations between specific variants and the percentage of weight lost following the surgery, and found that one specific variant at a site on chromosome 15 was closely associated with weight loss.

Those individuals who had two copies of the beneficial version of the gene had lost an average of nearly 40 percent of their pre-surgery weight, while those with just one copy lost approximately 33 percent. One individual that completely lacked the beneficial variant wound up losing less than 30 percent of pre-surgical weight.

“Expression of one of the genes closest to the site of this variant was also able to predict the percentage of weight lost,” the hospital explained. “In addition, experiments in a mouse model of gastric bypass indicated that expression of the corresponding version of that human gene, as well as another gene adjacent to the variant site, was altered by bypass surgery. Additional gene variants not as strongly associated with the response to bypass surgery are candidates for further study in larger groups of patients.”

Kaplan and his colleagues developed a pair of predictive models that showed promising initial results. One of those models combined the chromosome 15 gene variant with clinical factors like age, gender, and exercise behaviors. The other included 12 additional DNA variations that were studied for their usefulness in weight loss treatment planning.

They found that none of the predictive gene sites identified in this study were involved in pathways previously linked established to influence obesity. As a result, they believe that a different set of genes is responsible for the benefits of gastric bypass, and that the development of drugs targeting activity in those genetic regions could lead to some of the same benefits of the procedure without the need for surgery.

“Surgery is the most effective therapy for severe obesity, but these procedures are invasive, and not all patients get the same degree of benefit,” Kaplan said. “If we can identify those patients who are likely to lose more weight after surgery from those who do less well, we could help steer patients towards the therapy that best suits them.”

“This is the first instance where a genome-wide search has identified genetic predictors of weight loss after gastric bypass surgery,” he added. “Since the genes identified in this report have not previously been known to be involved with body-weight regulation and obesity, their identification may suggest new approaches that could be used to develop novel therapies for obesity, diabetes, and related metabolic disorders.”