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Disease and treatment

Surgery can counteract genetically determined obesity

For decades, there has been debate on whether expensive gastric bypass surgery is worthwhile for people who are genetically predisposed to being severely obese. However, the evidence does not support the concern that these people eventually regain the weight after surgery. In fact, obese people who are less genetically predisposed to being overweight more often tend to remain obese after surgery. The researchers think that social and cultural factors could explain this.

Gastric bypass surgery is still the most effective way to help severely obese people shed their dangerous extra kilos. The surgery can typically help people with life-threatening obesity shed about 40 kg and also eliminate such complications as diabetes. Nevertheless, this surgery is expensive, the anatomical changes are permanent and the procedure can pose a risk to the patient. The patient therefore needs to be thoroughly assessed before surgery. New research provides important input on who may benefit most from this surgery.

“We have examined the genes we know are associated to some extent with a high body mass index (BMI) to determine whether we could find any associations. Our data show that obese people genetically predisposed to have a high BMI are not more likely to remain obese after surgery. So previously there has been doubt as to whether people who are genetically predisposed to obesity would benefit from this surgery, but the opposite seems to be true,” explains a main author, Martin Aasbrenn, Guest Researcher, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Cause still unknown

To determine whether people with different genetic profiles respond uniformly to gastric bypass surgery, the researchers examined 577 people who were morbidly obese – before and after the surgery. They had either a BMI greater than 50 or a BMI between 35 and 50 with obesity-related complications.

“Based on previous knowledge from genetic studies of obesity, we compared three genetic risk scores – two for weight loss and one for BMI – to see whether we could find an association between the patients' genetic profile and how much weight they lost after surgery: not just shortly afterwards but lasting weight loss 2–3 years after surgery.”

The goal for the patients is to achieve a normal BMI of less than 25. However, because the patients do not always reach that target, the researchers examined the excess BMI loss, defined as the percentage change in BMI relative to the baseline. The patients had an average excess BMI loss of 77% – equivalent to their BMI declining from 47 to 30, for example.

“However, this average varied widely, and we found an association with the genetic risk scores and, most surprisingly, that the patients who were least genetically predisposed to having a high BMI lost a relatively smaller percentage of their BMI.”

The key 13 SNPs

In the example above, the BMI of a person with a low genetic predisposition for obesity might have declined from 47 to 32 instead of 30. Although this may seem like a relatively small difference, Martin Aasbrenn believes that this should be considered in assessing whether a person should be offered surgery.

“We cannot yet provide specific reasons for this difference. One theory is that people who are less genetically predisposed to become obese may have become obese for social or cultural reasons, and these reasons can only be eliminated by changing a person’s daily life and not through gastric bypass surgery.”

Although the researchers do not consider that their new results comprise a definitive basis for a new clinically usable assessment tool, they think their results are very clinically relevant.

“Most importantly, the findings refute the concern that gastric bypass surgery for people who are genetically predisposed to obesity is not cost-effective. In addition, our genetic analysis showed that some of the known genes are more important to consider than others in any genetic assessment.”

The researchers thus examined 126 positions in the genome called single-nucleotide polymorphisms (SNPs) that are associated with the size and shape of the human body. Of these, 13 were strongly associated with whether a person lost weight after bariatric surgery. Naturally, the researchers now want to try to understand why these 13 genes have the greatest association.

“In addition, we will continue to refine the genetic assessment tool to assess the potential effects of bariatric surgery. This is a step on the way to using genetic analysis clinically to determine whether a person should be offered gastric bypass surgery, and the method for deciding the type of treatment and possibly surgery based on a person’s genetic profile can probably also be used in other clinical contexts.”

“Genetic determinants of weight loss after bariatric surgery” has been published in Obesity Surgery. Several of the article’s authors are affiliated with the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. The research has been conducted in collaboration with Hvidovre Hospital.

Martin Aasbrenn
Guest researcher
The Hansen Group investigates the human genome and the human global microbiome to characterize the impact of these genomes on health and disease and to identify interactions between the host and the microbiome. The findings can lead to potent translational strategies for prevention and treatment of metabolic disease. In the molecular understanding of metabolic diseases a major gap exists between basic genetic and microbiome discoveries and their impact on physiology and the potential for clinical translation. The Hansen Group aims to bridge this gap by bringing together genomics discovery and epidemiology, culminating in a physiological and clinical understanding of genomics in metabolism. To study the role of selected genetic variants in human metabolism, we perform physiology and intervention studies based on recruit-by-genotype principles. We also investigate families and populations with extreme metabolic phenotypes and perform physiology and intervention studies in selected individuals with specific microbiome signatures. Finally, we investigate targeted clinical management of carriers of selected high-impact variations in the human genome.