- Unfavorable blood lipid levels, such as elevated levels of total cholesterol, LDL cholesterol, and triglycerides, and reduced levels of HDL cholesterol, have been associated with increased risk of CVDs (1–3). Lipid levels are determined by genetic and environmental factors, as well as their interactions (4, 5). There has been great interest in investigating cholesteryl ester transfer protein (CETP), a plasma glycoprotein that facilitates the transfer of cholesteryl ester and triglycerides between HDL and other lipoproteins (6), in relation to blood lipids. CETP deficiency due to CETP gene mutation causes increased HDL cholesterol levels (7, 8). In patients with low HDL cholesterol levels, CETP inhibition increased HDL cholesterol and decreased LDL cholesterol levels (9). Two previous meta-analyses have documented that CETP genetic variants related to moderate inhibition of CETP activity were associated with favorable blood lipid levels and decreased cardiovascular risk (10, 11). Several observational studies reported that CETP variants might interact with dietary factors, especially dietary fat intake, on HDL cholesterol levels (12–15), although the findings were not consistently replicated (11, 16–20). In addition, two small short-term diet intervention studies did not demonstrate the interaction between CETP genotype and dietary fat intake (21, 22). However, gene-diet interactions have rarely been investigated in long-term randomized intervention trials. Recent genome-wide association studies (GWASs) have shown stronger associations between CETP genetic variants with HDL cholesterol levels than any other loci across the human genome (23–27). A common variant, rs3764261, located 2.5 kb upstream of CETP exhibited a strong association with HDL cholesterol levels (3.39 mg/dl per A-allele, P = 7.0 × 10−380), and the HDL-decreasing allele was also associated with elevated levels of LDL cholesterol and triglycerides (P ≤ 1.1 × 10−12) (27). To our knowledge, no study has investigated the interaction between this GWAS-identified CETP variant and dietary intake on lipid levels. Identification of gene-lifestyle interactions in relation to lipid levels may help to clarify the mechanisms underlying the development of dyslipidemia and CVD, and provide effective strategies for disease prevention. Therefore, in the current study, we examined whether the CETP rs3764261 genotype modulated changes in lipid levels in response to weight-loss diets varying in fat content in a 2 year randomized intervention study: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) (28). We also replicated our findings in an independent 2 year intervention study: the Dietary Intervention Randomized Controlled Trial (DIRECT) (29).