CETP and APOA2 polymorphisms are associated with weight loss and healthy eating behavior changes in response to digital lifestyle modifications

Table of Contents

Overall results from prior studies

The general characteristics and the results regarding anthropometrics of the participants have been reported in elsewhere¹⁸. In summary, the mean percentage weight loss of participants in the dCBT-O group after 8 and 24 weeks was 3.1% and 3.7% of their initial weight, respectively. These results support the conclusion that the dCBT-O group exhibited a legacy effect even after the intervention was terminated. In addition, healthy dietary intake and diversity were shown to be promoted after dCBT-O. We found that the major predictors of clinical efficacy were depression, anxiety, self-esteem, motivation, restrained eating behavior, body shape satisfaction, and insulin resistance. Here, we aimed to investigate the role of genetic polymorphisms in the prediction of weight loss and related phenotypes.

Genotype frequency

In the present study, the genotype frequency stratified by each SNP, cholesterol ester transfer protein (CETP) rs9939224, and apolipoprotein A-II (APOA2) rs5082 genotypes are presented in Table 1. No significant deviation from HWE was observed (p > 0.05).

Table 1 Genotype and allele frequencies.

Associations with CETP rs9939224 and phenotypes

Regarding the primary outcome, the CETP GG genotype was shown to lead to a − 2.62% (p = 0.001) and − 2.91% (p = 0.020) variance in BMI after 8 and 24 weeks, respectively. The CETP T allele was shown to lead to a − 5.68% (p = 0.067) and − 9.94% (p = 0.042) variance in BMI after 8 and 24 weeks, respectively. Moreover, the CETP T allele was significantly associated with a greater BMI decrease at 24 weeks (p = 0.028; GG group BMI − 2.91%, GT group BMI − 9.94%; Fig. 2A). The CETP GG group exhibited a − 2.69% (p < 0.001) and − 2.56% (p = 0.029) change in weight after 8 and 24 weeks, respectively, while the CETP T allele group exhibited a − 5.48% (p = 0.077) and − 8.24% (p = 0.053) change in weight, respectively. Thus, the changes in weight were shown to exhibit a decreasing trend at 24 weeks in the CETP T allele group (p = 0.052; GG group weight change − 2.56%, GT group weight change − 8.24%; Fig. 2B). Finally, we found that the CETP GG group exhibited a − 5.65% (p < 0.001) and − 7.26% (p = 0.010) change in fat mass after 8 and 24 weeks, respectively, whereas the CETP T allele group exhibited a − 9.70% (p = 0.091) and − 20.78% (p = 0.054) change in fat mass at 8 and 24 weeks, respectively. Accordingly, the CETP T allele group presented a decreasing trend in regards to fat mass at 24 weeks (p = 0.057; GG group fat mass change − 7.26%, GT group fat mass change − 20.78%; Fig. 2C).

When considering dietary behaviors, we found that the CETP T allele group exhibited a significantly improved healthy diet diversity after dCBT-O when compared to the CETP GG group (p = 0.007; GG group Healthy diet diversity change 2.15% (p = 0.372), GT group Healthy diet diversity change 15.27% (p = 0.048); Fig. 2D). In addition, the CETP GG group demonstrated a − 5.83% (p = 0.141) and − 2.65% (p = 0.603) variance in emotional eating behavior after 8 and 24 weeks, respectively, while the CETP T allele group showed a − 2.5% (p = 0.921) and − 35% (p = 0.008) variance in emotional eating behavior after 8 and 24 weeks, respectively. Accordingly, emotional eating behavior (DEBQ-EM) was shown to be significantly promoted in the CETP T allele group at 24 weeks when compared to the CETP GG group (p = 0.007; GG group DEBQ-EM − 5.83%, GT group DEBQ-EM − 35%; Fig. 2E). Lastly, the CETP GG group showed a + 11.47% (p < 0.001) and + 5.53% (p = 0.040) variation in restrained eating behavior (DEBQ-RE) after 8 and 24 weeks, respectively, whereas the CETP T allele group exhibited a + 4.12% (p = 0.346) and + 4.80% (p = 0.429) variation in restrained eating behavior after 8 and 24 weeks, respectively. The change in restrained eating behavior in the CETP T allele group exhibited an increasing trend when compared to the CETP GG group at 24 weeks (p = 0.091; GG group DEBQ-RE + 5.53%, GT group DEBQ-RE + 4.80%; Fig. 2F). Any of the results did not pass the strict multiple comparison corrected P threshold.

Associations with APOA2 rs5082 and phenotypes

According to our analysis, the APOA2 AA group exhibited a − 3.93% (p < 0.001) and − 6.17% (p < 0.001) change in BMI after 8 and 24 weeks, respectively. The APOA2 AG group showed a 0.02% (p = 0.980) and + 2.05% (p = 0.222) change in BMI after 8 and 24 weeks, respectively. The APOA2 GG group showed a + 3.65% and + 5.11% change in BMI after 8 and 24 weeks, respectively. Thus, the APOA2 G allele was shown to be significantly associated with an increasing trend in BMI (p = 0.012 and p = 0.005 at 8 and 24 weeks, respectively; Fig. 3A). In addition, the APOA2 AA group showed a − 3.96% (p < 0.001) and − 5.39% (p < 0.001) change in weight at 8 and 24 weeks, respectively. On the other hand, the APOA2 AG group showed a − 0.03% (p = 0.967) and − 2.14% (p = 0.200) change in weight at 8 and 24 weeks, respectively, while the APOA2 GG group exhibited a + 3.65% and + 5.11% change in weight at 8 and 24 weeks, respectively. Therefore, the APOA2 G allele was shown to be associated with an increasing trend in weight (p = 0.01 and p = 0.004 at 8 and 24 weeks, respectively; Fig. 3B). In regards to changes in fat mass, the APOA2 AA group exhibited a − 7.47% (p < 0.001) and − 14.13% (p < 0.001) change in fat mass after 8 and 24 weeks, respectively, whereas the APOA2 AG and APOA2 GG groups presented a − 0.50% (p = 0.807) and − 4.31% (p = 0.084) and − 4.42% and + 12.05% change in fat mass, respectively, at 8 and 24 weeks. Therefore, the APOA2 G allele was associated with a significant increase in fat mass at 24 weeks (p = 0.0035) but not after 8 weeks (Fig. 3C). Regarding dietary behaviors, the APOA2 AA group exhibited a + 18.60% (p < 0.001) change in the proportion of healthy diet at 8 weeks, while the APOA2 AG group showed a − 10.02% (p = 0.365) change. The APOA2 GG group showed no change between the measurements taken at baseline and 8 weeks. Thus, the APOA2 AA genotype significantly promoted healthy diet proportions after dCBT-O when compared to the AG and GG genotype at 8 weeks post-intervention (p = 0.036; Fig. 3D). Any of the results did not pass the strict multiple comparison corrected P threshold.

SNP × SNP interaction

To test for a gene–gene effect between the CETP and APOA2 genotypes, they were classified into three interaction groups: best (good × good), intermediate (good × bad), and worst (bad × bad) response (shown in Fig. 4A,B). Linear regression analysis revealed that the primary outcome (BMI change) was significantly different between the three interaction genotype groups (p < 0.05). Moreover, the BMI change was significantly unfavorable in the worst-response group (+ 2.62%) when compared to both the intermediate (− 4.49%; p = 0.007) and best (− 11.45%; p = 0.038) response groups.

Associations with other SNPs and phenotypes

Several other SNPs were also associated with changes in clinical outcomes (Supplementary Table S1). For example, BMI change at 24 weeks, which was the primary outcome, was significantly associated with FTO rs1421084 (p = 0.044), LIPC rs1800588 (p = 0.004), and COMT rs737865 (p = 0.049). Furthermore, several SNPs were associated with the baseline phenotypes (Supplementary Table S2). For instance, MC4R rs17782313 was associated with anthropometric (body weight, p = 0.003; BMI, p = 0.001; body fat percentage, p = 0.014) and psychological measures (depression; p = 0.048) at baseline.