Gene-gene combination effect and interactions among ABCA1, APOA1, SR-B1, and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population

PLoS One. 2013 Dec 20;8(12):e82046. doi: 10.1371/journal.pone.0082046. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics*
  • Adult
  • Aged
  • Apolipoprotein A-I / genetics*
  • Asian People / genetics*
  • Cholesterol Ester Transfer Proteins / genetics*
  • Confidence Intervals
  • Epistasis, Genetic*
  • Female
  • Gene Frequency / genetics
  • Geography
  • Humans
  • Japan
  • Linear Models
  • Lipoproteins, HDL / blood*
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics*
  • Scavenger Receptors, Class B / genetics*

Substances

  • ABCA1 protein, human
  • APOA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Apolipoprotein A-I
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Lipoproteins, HDL
  • SCARB1 protein, human
  • Scavenger Receptors, Class B

Grants and funding

This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas of Cancer (No. 17015018) and Innovative Areas (No. 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.