title: Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers.
abstract: While alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol levels is unclear. Aldehyde dehydrogenase 2 (ALDH2) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers.
  
  
  
  This study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy.
  
  
  
  Alcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men (p < 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p < 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p < 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p < 0.001) and inversely associated with LDL particle numbers (-67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake.
  
  
  
  Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.
authors: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan; Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime 791-0295, Japan. Electronic address: tabara@genome.med.kyoto-u.ac.jp.
authors: Yasuharu
authors: Y
authors: Tabara
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Hirotsugu
authors: H
authors: Ueshima
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Naoyuki
authors: N
authors: Takashima
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Takashi
authors: T
authors: Hisamatsu
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Akira
authors: A
authors: Fujiyoshi
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Maryam
authors: M
authors: Zaid
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Masaki
authors: M
authors: Sumi
authors: Department of Regional Resource Management, Faculty of Collaborative Regional Innovation, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors: Katsuhiko
authors: K
authors: Kohara
authors: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan; Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime 791-0295, Japan.
authors: Tetsuro
authors: T
authors: Miki
authors: Department of Public Health, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors: Katsuyuki
authors: K
authors: Miura
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics; D000483:Alleles; D044466:Asian People; D050197:Atherosclerosis / Q000208:ethnology / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007564:Japan; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D010316:Particle Size
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D002784:Cholesterol; C096127:ALDH2 protein, human; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Alcohol consumption; Aldehyde dehydrogenase 2; Genotype; LDL cholesterol; LDL particles; Mendelian randomization analysis