Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-Loss Diets: The POUNDS LOST Trial
Background—Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) were recently related to insulin resistance and diabetes in prospective cohorts. We tested the effects of a genetic determinant of BCAA/AAA ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.
Methods and Results—We genotyped a BCAA/AAA ratio associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to one of four diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), after adjustment for the confounders (all P for interaction ≤ 0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern); while an opposite genotype effect on changes in insulin and HOMA-IR was observed in low-fat diet group (P = 0.02 and 0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (P = 0.008), but became null for changes in serum insulin and HOMA-IR due to weight regain.
Conclusions—Individuals carrying the C allele of a BCAA/AAA ratio associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet.
Clinical Trial Registration Information—http://www.clinicaltrials.gov. Identifier: NCT00072995.
- Branched-chain amino acids
- gene-diet interaction
- weight loss
- amino acids
- body weight
- insulin resistance
- genetic epidemiology
- clinical trial
- Received December 11, 2012.
- Revision received February 2, 2013.
- Accepted February 14, 2013.