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.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Niimura
authors.affiliation: Education Center for Doctors in Remote Islands and Rural Areas, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kuwabara
authors.affiliation: Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Takezaki
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Morita
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakai
authors.affiliation: Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hamajima
authors.affiliation: Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Health Science, Shiga University of Medical Science Otsu, Japan ; Department of Medicine, University of Calgary, Calgary, Canada.
authors.forename: Tanvir Chowdhury
authors.initials: TC
authors.lastname: Turin
authors.affiliation: Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Sadao
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Ohnaka
authors.affiliation: Department of Preventive Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Uemura
authors.affiliation: Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ozaki
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Satoyo
authors.initials: S
authors.lastname: Hosono
authors.affiliation: Division of Cancer Registry, Prevention and Epidemiology, Chiba Cancer Center, Chiba, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Mikami
authors.affiliation: Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D016001:Confidence Intervals; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005843:Geography; D006801:Humans; D007564:Japan; D016014:Linear Models; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051122:Scavenger Receptors, Class B / Q000235:genetics*
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B