Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-Loss Diets

Background— Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial. Methods and Results— We genotyped the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 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), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group ( P =0.02 and P =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 resulting from weight regain. Conclusions— Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid 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— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00072995.