Genetics
CETP rs3764261 T allele is the top single-locus HDL-C predictor among 13 SNPs in a 3,050-person Japanese cohort (PLoS One 2013)
Original title: Gene-gene combination effect and interactions among ABCA1, APOA1, SR-B1, and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population
Researchers examined gene-gene combination effects among 13 SNPs in ABCA1, APOA1, CETP, and SR-B1, genes in the reverse cholesterol transport pathway, for their association with HDL cholesterol (HDL-C) in 1,535 men and 1,515 women from the Japan Multi-Institutional Collaborative Cohort Study. Alcohol consumption and daily activity were positively associated with HDL-C and smoking negatively so, but the CETP rs3764261 T allele had the highest coefficient of all 13 SNPs (2.93 mg/dL per allele), remaining significant after Bonferroni correction (p<0.001). Gene-gene combination analysis found CETP rs3764261 was associated with high HDL-C regardless of which ABCA1, APOA1, or SR-B1 genotype combination it appeared with, though no formal gene-gene interaction was detected, and HDL-C rose with an increasing number of favorable alleles (p<0.001). The authors conclude CETP rs3764261 exerts a multiplier effect with the other three genes and a dose-dependent relationship with allele count.
Original abstract
Background/Objective: Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population.
Methods: The study population comprised 1,535 men and 1,515 women aged 35-69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region.
Principal Findings: Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001).
Conclusions: The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.