Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers

Background and aims: 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. Methods: 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. Results: 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 mmol/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. Conclusions: Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers. (C) 2016 Elsevier Ireland Ltd. All rights reserved.