Genetics
The CETP rs708272 risk allele is linked to higher cardiac gene expression and interacts with diet and smoking to triple the risk of low HDL (Front Nutr 2023)
Original title: Interaction of energy and sulfur microbial diet and smoking status with polygenic variants associated with lipoprotein metabolism
This study examined whether polygenic variants for low HDL cholesterol (hypo-HDL-C) interact with lifestyle factors in 58,701 middle-aged Korean adults from the Korean Genome and Epidemiology Study, comparing 16,980 participants with hypo-HDL-C to 41,721 with normal HDL. Participants with hypo-HDL-C showed 1.45-fold and 1.36-fold higher associations with myocardial infarction and stroke respectively. A high polygenic risk score built from four SNPs, including CETP_rs708272, was positively associated with hypo-HDL-C by about 3-fold, a 2.4-fold stronger association than a broader 24-SNP score. The risk allele of CETP_rs708272 was specifically linked to increased gene expression in the heart, and this 4-SNP polygenic risk score interacted with energy intake and smoking status, indicating that adults carrying the CETP risk variant may need to modulate diet and smoking to reduce their genetic risk of low HDL cholesterol.
Original abstract
Introduction: Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES).
Methods: Participants were categorized into the Low-HDL (case; n = 16,980) and Normal-HDL (n = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (<40 mg/dL for men and < 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters.
Results: The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely ZPR1_rs3741297, CETP_rs708272, BUD13_rs180327, and ALDH1A2_rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with p < 5×10-8. The risk alleles of CETP_rs708272 and ALDH1A2_rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status.
Discussion: Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.