Genes Foretell Weight Loss After Surgery

Weight loss after gastric bypass surgery correlated significantly with a genetic variant tracked to chromosome 15, according to a study involving more than 1,000 patients.

Patients with a single copy of the minor allele known as rs17702901 had about 13% less weight loss compared with individuals who had no copies of the allele.

Postoperative expression of the gene nearest to rs17702901 also correlated with weight loss. None of 21 other single nucleotide polymorphisms (SNPs) or nearby genes had significant associations with weight loss after surgery, Lee M. Kaplan, MD, of Massachusetts General Hospital and Harvard, and co-authors reported online in the American Journal of Human Genetics.

"We have identified a genetic locus that is reproducibly associated with weight loss after Roux-en-Y gastric bypass (RYGB)," the authors concluded. "This study provides evidence for the use of genomics to identify response to surgical procedures (surgicogenomics).

"Comparison of genetic predictors identified for RYGB with those identified for other weight-loss procedures could provide insight into their shared and distinct mechanisms of action."

An accumulation of evidence has suggested that RYGB induces weight loss by various physiologic mechanisms, as opposed to strictly mechanical effects. Kaplan and colleagues previously reported that genetically related individuals who lived separately and underwent RYGB had similar weight-loss outcomes. In contrast, genetically unrelated individuals who lived together had outcomes after RYGB similar to those of randomly paired controls (J Clin Endocrinol Metab 2011; 96: E1630-E1633).

The observations suggested that as much of 70% of the variability in weight loss after RYGB might be explained by genetic factors. Although specific factors have not been found, identifying them would improve the odds of selectively targeting RYGB to patients who might benefit most, the authors continued.

In an effort to uncover genetic influences on RYGB outcomes, investigators performed a genome-wide association study involving 1,018 patients who underwent the weight-loss surgery from February 2000 until April 2007. The study population included an initial group of 693 patients and a validation cohort of 327 patients.

Kaplan and colleagues performed an association analysis between 1,943,170 SNPs and percent excess weight loss the the patients' nadir weight after surgery. They initially identified 102 marginally significant SNPs, and after subsequent evaluations, genotyped 22 of the SNPs.

Pooled analysis of data from the initial and validation cohorts identified rs17702901 at locus 15q26.1 as having a significant association with weight loss (P=0.0020). An additional 13 SNPs demonstrated trends toward associations that did not achieve statistical significance. On average, patients with a single copy of rs17702901 (N=52) lost 33.5% of excess weight compared with 38.7% for individuals who had no copies.

The only patient with two copies of rs17702901 lost 28.8% of excess weight.

The authors found that patients with a single copy of rs17702901 were 2.54 times more likely to lose ?30% of excess weight (P<0.0001 versus no copies) and that no patient with a minor allele lost ?50% of excess weight.

The rs17702901 genotype explained 2.8% of the variance in weight loss.

Investigators also examined the relationship between weight loss and expression of the two genes nearest to rs17702901 (ST8SIA2 and SLCO3A1). Increased expression of ST8SIA2 in omentum fat -- but not liver or subcutaneous fat -- was significantly associated with percent weight loss, and the association persisted after adjustment for rs17702901 genotype (P=0.007). SLCO3A1 expression had no significant associations with weight loss.

The authors noted that other SNPs near ST8SIA2 associated with autism, bipolar disorder, and schizophrenia.

Despite providing evidence of genetic influence on the effects of RYGB, the authors said the results are not yet ready to apply in clinical practice.

"The gene(s) responsible for correlation between rs17709201 and postoperative weight loss should provide additional insight into the mechanisms of action of RYGB and elucidate potential targets for obesity therapies," they said. "Given the wide distribution of outcomes after RYGB, including in individuals carrying the rs17702901 minor allele, we cannot recommend that rs17702901 allele status, in isolation, be used as an exclusion criteria for surgical therapy."

Primary source: American Journal of Human Genetics
Source reference:
Hatoum IJ, et al "Weight loss after gastric bypass is associated with a variant at 15q26.1" Am J Hum Genetics 2013; DOI: 10.1016/j.ajhg.2013.04.009.