TY - JOUR
T1 - Functional variants in ADH1B and ALDH2 are non-additively associated with all-cause mortality in Japanese population
AU - Sakaue, Saori
AU - Akiyama, Masato
AU - Hirata, Makoto
AU - Matsuda, Koichi
AU - Murakami, Yoshinori
AU - Kubo, Michiaki
AU - Kamatani, Yoichiro
AU - Okada, Yukinori
N1 - Funding Information:
Acknowledgements This research was supported by the Tailor-Made Medical Treatment program (the BioBank Japan Project) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED), Bioinformatics Initiative of Osaka University Graduate School of Medicine, and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University. Y.O. was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15H05911, 19H01021), AMED (19gm6010001h0004, 19ek0410041h0003, 19km0405211h0001, and 19ek0109413h0001).
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/3/1
Y1 - 2020/3/1
N2 - The functional variants involved in alcohol metabolism, the A allele of rs1229984:A > G in ADH1B and the A allele of rs671:G > A in ALDH2, are specifically prevalent among East Asian population. They are shown to be under recent positive selection, but the reasons for the selection are unknown. To test whether these positively selected variants have beneficial effects on survival in modern population, we performed the survival analyses using the large-scale Japanese cohort (n = 135,974) with genotype and follow-up survival data. The rs671-A allele was significantly associated with the better survival in the additive model (HR for mortality = 0.960, P = 1.7 × 10−5), and the rs1229984-A had both additive and non-additive effects (HR = 0.962, P = 0.0016 and HR = 0.958, P = 0.0066, respectively), which was consistent with the positive selection. The favorable effects of these alleles on survival were independent of the habit of alcohol consumption itself. The heterogenous combinatory effect between rs1229984 and rs671 genotype was also observed (HRs for AA genotype at rs671 were 1.03, 0.80, and 0.90 for GG, GA, and AA genotype at rs1229984, respectively), supposedly reflecting the synergistic effects on survival.
AB - The functional variants involved in alcohol metabolism, the A allele of rs1229984:A > G in ADH1B and the A allele of rs671:G > A in ALDH2, are specifically prevalent among East Asian population. They are shown to be under recent positive selection, but the reasons for the selection are unknown. To test whether these positively selected variants have beneficial effects on survival in modern population, we performed the survival analyses using the large-scale Japanese cohort (n = 135,974) with genotype and follow-up survival data. The rs671-A allele was significantly associated with the better survival in the additive model (HR for mortality = 0.960, P = 1.7 × 10−5), and the rs1229984-A had both additive and non-additive effects (HR = 0.962, P = 0.0016 and HR = 0.958, P = 0.0066, respectively), which was consistent with the positive selection. The favorable effects of these alleles on survival were independent of the habit of alcohol consumption itself. The heterogenous combinatory effect between rs1229984 and rs671 genotype was also observed (HRs for AA genotype at rs671 were 1.03, 0.80, and 0.90 for GG, GA, and AA genotype at rs1229984, respectively), supposedly reflecting the synergistic effects on survival.
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U2 - 10.1038/s41431-019-0518-y
DO - 10.1038/s41431-019-0518-y
M3 - Article
C2 - 31558841
AN - SCOPUS:85074007847
VL - 28
SP - 378
EP - 382
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 3
ER -