For severely overweight patients, bariatric surgery can work remarkably well—though not necessarily for the reasons one might suspect. Rather than by physically restricting food, gastric bypass and related surgeries work primarily through physiological effects, such as regulating appetite and satiety.

The amount of weight people lose after Roux-en-Y gastric bypass (RYGB) varies. All else being equal, some patients lose a lot of weight, some lose very little, but most lose an average amount postsurgery.

But why?

According to new research out of Massachusetts General Hospital, it could be genetic.

Scientists at Mass General, Harvard Medical School, Merck Research Laboratories, and the Broad Institute identify a variant at 15q26.1 that is significantly associated with weight loss after RYGB.

In a genomewide association study involving 693 people undergoing bypass surgery, and a replication study including 327 additional surgical patients, Mass General’s Lee Kaplan and his colleagues found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was associated with postsurgical weight loss.

More specifically, the team found that people who had two copies of the so-called beneficial variant lost nearly 40% of their presurgical weight on average, while those with only one copy lost closer to 33%. One patient involved in the study had no copies of the variant and lost less weight still.

In follow-up work on RYGB and weight-matched, sham-operated mice, Kaplan’s team found expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in postsurgical mice, compared with their control counterparts. “These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB,” the authors wrote.

In a statement, Kaplan, who directs the MGH Weight Center, pointed to some of the study’s other potential implications.

“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 said. “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 added.

Overall, the researchers suggest that having found genes involved in post-bariatric surgery weight loss is an important first step for developing new ways to combat obesity.

“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,” Kaplan said.

The study appears this week in The American Journal of Human Genetics, in a paper titled “Weight Loss after Gastric Bypass Is Associated with a Variant at 15q26.1”.

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