Genetic Predictors of Behavioral Weight Loss: Current Status and Future Directions.

Abstract

In this issue of Obesity, Hollensted and colleagues (1) report on their analysis of whether genetic loci previously implicated in childhood obesity predict the magnitude of weight loss with lifestyle intervention among 754 children and adolescents with overweight. Genetic risk scores combining 15 single-nucleotide polymorphisms (SNPs) from the most recent genome-wide association studies (GWAS) did not significantly predict change in BMI standard deviation score during the intervention. One of the 15 SNPs, LMX1B rs3829849, did predict weight loss independently. This study represents an important advance in understanding whether known genetic predictors of childhood BMI may inhibit children from losing weight with lifestyle methods. It is the largest study to date, tested a comprehensive list of the most recent genetic variants associated with childhood BMI, employed an evidence-based weight-loss intervention, and achieved a median weight loss of 0.20 BMI standard deviation score or roughly 10% weight loss. It should be noted that weight loss was reported at varying time points (follow-up: 6-24 months; median: 1.25 years). In addition, children who did not complete a minimum of 6 months of the program were excluded. These factors could have created variability in measurement of BMI and/or bias from excluding those who were not successful, potentially limiting the detection of genetic effects. Nonetheless, these results contribute to a growing literature indicating that SNPs related to BMI in GWAS largely do not appear to predict the magnitude of weight loss in behavioral interventions. Prominent examples include a lack of association of the FTO region with weight loss in a meta-analysis including 9,563 participants (2). In a joint analysis of the Action for Health in Diabetes (Look AHEAD) trial and the Diabetes Prevention Program (DPP), only one of a comprehensive list of 91 SNPs predicted magnitude of weight loss in the lifestyle interventions (3). MC4R mutations causing monogenic obesity also did not predict magnitude of weight loss with lifestyle intervention in children (4). That said, the progress in identifying genetic variation predictive of weight loss should be recognized. In the meta-analysis of Look AHEAD and DPP, the obesity-related allele of MTIF3 rs1885988 predicted greater weight loss. One copy of the obesity risk allele conferred an additional loss of 1.48 kg, and two copies predicted a 2.96-kg weight loss (3). Moreover, using a gene-centric assay, ABCB11 and RANK were shown to relate to magnitude of weight loss in Look AHEAD (5). In the Hollensted et al. paper, LMX1B rs3829849 also significantly predicted weight loss. Although not yet of sufficient magnitude to guide clinical recommendations, such findings provide a platform for replication and extension with increasing sample sizes and may ultimately be employed as part of a weight-loss genetic risk score. It is noteworthy that the search for genetic predictors of weight loss has been limited almost exclusively to SNPs related to BMI in GWAS. No genome-wide analysis of weight loss has been conducted, but it could lead to the discovery of novel genetic loci related to weight loss, as was observed for bariatric surgery (6). Such new discoveries could ultimately contribute to a genetic risk score sufficiently predictive of weight loss for clinical application. JMM reports personal fees from Weight Watchers, outside the submitted work.