Differential weight-loss responses of APOA2 genotype carriers to low-carbohydrate and low-fat diets: the DIETFITS trial.

OBJECTIVE

This study aimed to determine whether APOA2 genotypes and saturated fatty acid (SAT) intake affect weight-loss response to healthy low-carbohydrate (HLC) and healthy low-fat (HLF) diets.

METHODS

This is a secondary analysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) study, a 12-month randomized clinical trial of HLC or HLF diets in 609 adults aged 18 to 50 years with BMI values between 28 and 40 kg/m. The current study examined 3-, 6-, and 12-month weight loss in participants with different APOA2 genotypes (TT vs. C allele carriers, CT + CC) at variant rs5082 who met the SAT intake criterion of ≥22 g/day for an HLC diet and < 22 g/day for an HLF diet at all three study time points.

RESULTS

Participants with the TT APOA2 genotype lost significantly more weight consistently on an HLC diet than on an HLF diet at 3, 6, and 12 months, whereas C allele carriers lost more weight only at 3 months and not at 6 or 12 months. APOA2 genotype-by-SAT intake interaction affecting weight loss was observed only at 12 months. Among participants who did not consistently meet the SAT intake criterion, there were no significant weight-loss differences among APOA2 genotypes.

CONCLUSIONS

This study highlights the importance of evaluating genotype-diet interactions in weight-loss trials to better inform precision nutrition interventions.

CLINICAL TRIAL REGISTRATION

NCT01826591.

© 2025 The Obesity Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.