Study assessed nature and nurture

Genetics can’t necessarily be blamed for excess weight in kids, according to a study from Germany, which suggested that genes played a minor role in weight reduction by lifestyle in children who were overweight or obese.

In the LOGIC study, five of 56 obesity single-nucleotide variants (SNVs) were statistically significantly tied to a reduction of body weight or BMI (P <8.93×10−4 corresponding to Bonferroni correction for 56 tests), reported Melanie Heitkamp, PhD, Technical University of Munich, and co-authors.

And, after an inpatient lifestyle intervention, mean decreases were noted in body weight (−8.7 kg, 95% CI −15.7 to −1.8 kg), and BMI (−3.3 kg, 95% CI −5.4 to −1.1, P<0.05 for both), they stated in JAMA Pediatrics.

Heitkamp’s group also found that weight loss achieved through the intervention varied, depending on five risk alleles in particular.

“To our knowledge, this is the largest interventional study in children and adolescents with overweight or obesity investigating the association of genetics with the outcome of a standardized lifestyle intervention program,” they wrote. “This study suggests that environmental, social, and behavioral factors play the most important role in obesity treatment strategies in children, whereas genetics are secondary.”

The authors acknowledged that because LOGIC was not a randomized, controlled trial — it would have been “ethically questionable by randomizing treatment-seeking overweight and obese individuals into a no-treatment group or wait-list control group,” they explained — the results cannot determine causality.

The take-home message from the authors is that “Genes appear to play a minor role in weight reduction by lifestyle in children with overweight or obesity,” and the change in body weight was very small (0.7 kg or 1.5 lbs.), if in fact it exists at all, agreed Ann Chen Wu, MD, MPH, and Marie-France Hivert, MD, MMSc, both of Harvard Medical School and Harvard Pilgrim Health Care Institute in Boston, in an editorial accompanying the study.

But the findings “will require validation in other weight management intervention studies and usefulness in other settings (outpatients) and populations (other countries and race/ethnicities),” Wu and Hivert stated, and then be assessed in the context of earlier research in adults, such as the Diabetes Prevention Program and Look AHEAD study, a Danish study, and the HUNT study.

LOGIC was an interventional, prospective cohort study that enrolled 1,429 children who were overweight or obese in an in-hospital lifestyle intervention program from 2006 to 2013. Genotyping of 56 validated obesity SNVs was done, and the authors looked at the links between SNVs and body weight reduction during the intervention. Of the total patient population, 1,198 individuals (mean age 14 years; 56% girls) were genotyped. The data were evaluated using linear mixed-effects models for each SNV and analyzed from 2015 to 2016.

Wu and Hivert pointed out that “the 56 loci investigated is larger than the number in similar studies; however, it is still a small number compared with the current knowledge of more than 900 genetic variants known to be associated with BMI.”

As for the intervention, it was a 4-to-6-week standardized in-hospital program that involved daily physical activity, calorie-restricted diet, and behavioral therapy, and it was conducted in line with German guidelines for inpatient weight loss programs, according to the authors.

Wu and Hivert highlighted that the inpatient setting “limits the generalizability of [the study’s] findings, as many weight management programs are offered in the outpatient setting.”

The authors reported that, compared with homozygous participants without the risk allele, homozygous carriers of the rs7164727 and rs12940622 risk alleles had a lower reduction of body weight:

  • LOC100287559 (“Overall knowledge… is scarce”): 0.42 kg (95% CI 0.31 to 0.53 kg, P=4.00×10−4).
  • RPTOR (“encodes a component of a signaling pathway that regulates cell growth in response to nutrient and insulin levels”): 0.35 kg (95% CI 0.18 to 0.52 kg, P=1.86×10−5).

Also, compared with homozygous participants without the risk allele, carriers of the rs13201877 and rs10733682 risk alleles were associated with a greater reduction of body weight after adjustment for age and sex:

  • IFNGR1 (“associated with susceptibility to mycobacterial disease”): 0.65 kg (95% CI 0.51 to 0.79 kg, P=2.39×10−5).
  • LMX1B (“a transcription factor [that] is essential… for the dopaminergic and serotonergic neurons”): 0.45 kg (95% CI 0.27 to 0.63 kg, P=6.37×10−4).
  • ETS2 (“encodes a transcription factor, which regulates genes involved in development and apoptosis”): 0.56 kg (95% CI 0.38 to 0.74 kg, P=1.51×10−4).

Wu and Hivert noted that the authors “were…not able to include all currently known variants specifically associated with childhood obesity and had poor coverage of the known FTO variants (the most replicated loci for obesity in adult and childhood).”

However, the authors explained that “We could not find any associations between weight loss and… FTO. However, this lack of association refers especially for FTO caused by low coverage because the tag SNVs… of FTO were not available in our data set owing to technical reasons.” Nonetheless, an analysis of FTO SNVs rs17817449 and rs3751812 still showed “no association with weight loss,” they reported.

  1. Five of 56 obesity single-nucleotide variants were statistically significantly associated with changes in body weight, but only to a minor degree, in overweight or obese children enrolled in an inpatient lifestyle intervention.

  2. The 56 loci investigated in the LOGIC trial were larger than the number evaluated in similar studies, but still a small number versus the current knowledge of more than 900 genetic variants known to be tied to BMI.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by Else Kröner-Fresenius-Stiftung Bad Homburg, Germany and supported by the Deutsche Rentenversicherung Bayern Sued.

Heitkamp and co-authors, along with Hivert, reported no relationships relevant to the contents of this paper to disclose.

Wu reported support from GlaxoSmithKline.

Cat ID: 496

Topic ID: 495,496,496,497,795,138,140,477,518,917