Weight gain prevention buffers the impact of CETP rs3764261 on high density lipoprotein cholesterol in young adulthood: The Study of Novel Approaches to Weight Gain Prevention (SNAP)

Two weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. Participants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for ≥ 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). The C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. clinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/ •Randomized weight gain prevention strategies blunted the impact of CETP rs3764261, representing the region mostly strongly associated with high density lipoprotein cholesterol (HDL-C) in genome-wide association studies, on lowering of HDL-C over two years in young adulthood.•Even among those with the highest risk genotype for low HDL-C, the CC genotype, randomized weight gain prevention produced an increase in HDL-C whereas lowering was observed in the control group.•Obesity-related genetic variants, either independently or interaction with treatment arm, did not predict weight change.