TY - JOUR
T1 - Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers
AU - Tabara, Yasuharu
AU - Ueshima, Hirotsugu
AU - Takashima, Naoyuki
AU - Hisamatsu, Takashi
AU - Fujiyoshi, Akira
AU - Zaid, Maryam
AU - Sumi, Masaki
AU - Kohara, Katsuhiko
AU - Miki, Tetsuro
AU - Miura, Katsuyuki
N1 - Funding Information:
This study was supported by Grants-in-aid for Scientific Research (A) 13307016 , (A) 17209023 , (A) 21249043 , (A) 23249036 , (A) 25253046 (B) 25293141 , (B) 24390084 , (B) 21390099 , (B) 20390185 and (priority area) 20018020 from the Ministry of Education, Culture, Sports, Science, and Technology Japan , by grant R01HL068200 from the National Institutes of Health , and by Glaxo-Smith Klein .
Publisher Copyright:
© 2016 Elsevier Ireland Ltd
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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 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. Conclusions Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.
AB - 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 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. Conclusions Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.
KW - Alcohol consumption
KW - Aldehyde dehydrogenase 2
KW - Genotype
KW - LDL cholesterol
KW - LDL particles
KW - Mendelian randomization analysis
UR - http://www.scopus.com/inward/record.url?scp=85027926660&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027926660&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2016.08.021
DO - 10.1016/j.atherosclerosis.2016.08.021
M3 - Article
C2 - 27575649
AN - SCOPUS:85027926660
SN - 0021-9150
VL - 254
SP - 242
EP - 248
JO - Atherosclerosis
JF - Atherosclerosis
ER -