The causal effects of alcohol on lipoprotein subfraction and triglyceride levels using a Mendelian randomization analysis: The Nagahama study.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.