title: The causal effects of alcohol on lipoprotein subfraction and triglyceride levels using a Mendelian randomization analysis: The Nagahama study.
abstract: Light-to-moderate alcohol consumption may increase circulating high-density lipoprotein cholesterol (HDL-C) levels and decrease low-density lipoprotein cholesterol (LDL-C) levels. However, the effect of alcohol on biologically important lipoprotein subfractions remains largely unknown. Here we aimed to clarify the effects of alcohol on lipoprotein subfractions using a Mendelian randomization analysis.
  
  
  
  The study subjects consisted of 8364 general Japanese individuals. The rs671 polymorphism in aldehyde dehydrogenase 2 gene, a rate-controlling enzyme of alcohol metabolism, was used as an instrumental variable. Lipoprotein subfractions were measured by a homogeneous assay.
  
  
  
  The biologically active *1 allele of the ALDH2 genotype was strongly associated with alcohol consumption in men (p < 0.001). In a regression analysis adjusted for possible covariates, the *1 allele was positively associated with HDL-C even in a sub-analysis for HDL subfractions (HDL2-C: β = 0.082, p < 0.001; HDL3-C: β = 0.195, p < 0.001). In contrast, the *1 allele was inversely associated with total LDL-C levels (β = -0.049, p = 0.008), while its association with large-buoyant LDL-C (β = -0.124, p < 0.001) and small-dense LDL-C (β = 0.069, p < 0.001) was opposite. Therefore, the ratio of small-dense LDL to large-buoyant LDL exhibited a linear increase with the number of *1 alleles carried (β = 0.127, p < 0.001). Furthermore, the *1 allele was inversely associated with triglyceride levels in an analysis adjusted for LDL subfractions (β = -0.097, p < 0.001), but not for the total LDL (β = 0.014, p = 0.410).
  
  
  
  Alcohol may increase HDL-C levels irrespective of the particle size. Moreover, alcohol may decrease the total LDL-C, although the proportion of atherogenic small-dense LDL-C increased partially due to a potential inter-relationship with decreased triglyceride levels.
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: tabara@genome.med.kyoto-u.ac.jp.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.affiliation: National Center for Geriatrics and Gerontology, Obu, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.affiliation: Research and Development Center, Denka Seiken Co., Ltd., Tokyo, Japan.
authors.forename: Yuhko
authors.initials: Y
authors.lastname: Hirao
authors.affiliation: Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Setoh
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kosugi
authors.affiliation: Research and Development Center, Denka Seiken Co., Ltd., Tokyo, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000097:blood*; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D015536:Down-Regulation; D000431:Ethanol / Q000097:blood* / Q000378:metabolism; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D010316:Particle Size; D011110:Polymorphism, Genetic; D014280:Triglycerides / Q000097:blood*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; D000431:Ethanol; C096127:ALDH2 protein, human; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Alcohol consumption; High-density lipoprotein; Lipoprotein subfractions; Low-density lipoprotein; Mendelian randomization analysis