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Genes predict weight loss post gastric bypass

Findings could help to guide treatment and facilitate the development of new therapeutic approaches for obesity

The amount of weight loss after this gastric bypass surgery can be predicted in part by a DNA sequence variation found on chromosome 15, according to a genome-wide association study by Massachusetts General Hospital researchers published in the The American Journal of Human Genetics.

Dr Lee Kaplan

"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," said Dr Lee Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts and senior author of the report. "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."

The investigators claim that the findings explain why the success of gastric bypass surgery varies so widely and could help clinicians identify those who would benefit the most from this type of surgery, and could help to guide treatment planning and to facilitate the development of new therapeutic approaches to treating obesity and related conditions like diabetes.

The research team conducted genome-wide association studies of more than 1,000 patients who had bypass surgery at the MGH from 2000 to 2011, analysing almost two million gene sites for associations between specific variants and the percentage of weight lost after surgery.

They performed a genome-wide association study of 693 individuals undergoing bypass and then replicated this analysis in an independent population of 327 individuals undergoing bypass.

One specific variant at a site on chromosome 15 (15q26.1 locus near ST8SIA2 and SLCO3A1) was most closely associated with weight loss. Individuals with two copies of the beneficial version of the gene lost an average of almost 40% of their pre-surgical weight, while those with only one copy lost around 33%. The single individual in the study group who had no copies of the beneficial variant lost less than 30% of pre-surgical weight.

Expression of ST8SIA2 in omental fat of individuals with two copies of the beneficial version of the gene at baseline was significantly associated with weight loss after bypass. Gene expression analysis in bypass and weight-matched, sham-operated mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to sham-operated mice.

Additional gene variants not as strongly associated with the response to bypass surgery are candidates for further study in larger groups of patients.

Two predictive models developed by Kaplan and his team have had promising initial results. One of these combines the chromosome 15 genetic variant with clinical factors such as age, gender, the presence of diabetes and exercise behaviors to predict surgical outcomes; the other includes 12 additional gene variants the investigators are studying to determine their usefulness in treatment planning.

Interestingly, none of the predictive gene sites identified in this study are involved in pathways previously known to influence the development of obesity, suggesting that different genes contribute to the benefits of bypass.

Development of drugs that target the activity of those genes might produce some of the same benefits without the need for surgery, said Kaplan.

"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," he said. "Identifying the involved genes opens up the potential for new classes of anti-obesity therapies that mimic or exploit the molecular mechanisms so effectively used by gastric bypass."

Dr Kaplan has previously reported that changing gut microbiota is a significant contributor to weight loss following gastric bypass.

Next article: EU project to investigate neurology and eating behaviour

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