title: Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians.
abstract: Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10(-56) and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1 × 10(-44) and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 × 10(-28) for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.
authors.affiliation: Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511, USA. dawei.li@yale.edu
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000235:genetics*; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D060467:Disease Resistance / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000235:genetics; D010195:Pancreatitis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
references.citation: Genet Med. 2009 Oct;11(10):695-706
references.pmid: 19773668
references.citation: Biometrics. 2000 Jun;56(2):455-63
references.pmid: 10877304
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):561-569
references.pmid: 19655364
references.citation: Alcohol Alcohol. 1994 Nov;29(6):707-10
references.pmid: 7695788
references.citation: Alcohol Clin Exp Res. 2010 Jul;34(7):1212-8
references.pmid: 20477771
references.citation: Alcohol Clin Exp Res. 2009 May;33(5):839-47
references.pmid: 19298323
references.citation: Control Clin Trials. 1986 Sep;7(3):177-88
references.pmid: 3802833
references.citation: Arch Intern Med. 2008 May 26;168(10):1077-89
references.pmid: 18504336
references.citation: Alcohol Clin Exp Res. 2009 May;33(5):799-803
references.pmid: 19298328
references.citation: Addiction. 1993 Jun;88(6):791-804
references.pmid: 8329970
references.citation: Hum Genet. 2009 Jul;126(1):91-9
references.pmid: 19533172
references.citation: Hypertens Res. 2009 Mar;32(3):207-13
references.pmid: 19262484
references.citation: West Indian Med J. 2009 Mar;58(2):164-72
references.pmid: 20953317
references.citation: Am J Med Genet. 2002 Jun 1;110(1):45-50
references.pmid: 12116270
references.citation: Addiction. 1994 Dec;89(12):1629-38
references.pmid: 7866247
references.citation: Life Sci. 1995 Feb 17;56(13):1121-6
references.pmid: 9001446
references.citation: J Neural Transm (Vienna). 2002 Apr;109(4):513-21
references.pmid: 11956970
references.citation: Hepatology. 2006 Feb;43(2):352-61
references.pmid: 16440362
references.citation: Chin Med J (Engl). 2002 Jul;115(7):1085-7
references.pmid: 12173598
references.citation: Prog Nucleic Acid Res Mol Biol. 1991;40:255-87
references.pmid: 2031085
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 5;147B(2):174-8
references.pmid: 17894408
references.citation: Biometrics. 1994 Dec;50(4):1088-101
references.pmid: 7786990
references.citation: Behav Brain Funct. 2008 Sep 18;4:42
references.pmid: 18801187
references.citation: Hum Genet. 1995 Aug;96(2):151-4
references.pmid: 7635462
references.citation: Eur Neuropsychopharmacol. 2006 Feb;16(2):123-8
references.pmid: 16125912
references.citation: Hum Genomics. 2009 Apr;3(3):213-20
references.pmid: 19403456
references.citation: Hum Mol Genet. 2009 Feb 1;18(3):580-93
references.pmid: 18996923
references.citation: Zhonghua Gan Zang Bing Za Zhi. 2003 Nov;11(11):654-6
references.pmid: 14636437
references.citation: Hum Genet. 1996 Apr;97(4):431-4
references.pmid: 8834237
references.citation: Alcohol. 2004 Oct-Nov;34(2-3):115-20
references.pmid: 15902904
references.citation: Psychiatry Res. 2001 Oct 10;104(1):19-26
references.pmid: 11600186
references.citation: Hepatology. 1997 Jan;25(1):112-7
references.pmid: 8985275
references.citation: Bioinformatics. 2008 Dec 15;24(24):2938-9
references.pmid: 18974171
references.citation: Alcohol Clin Exp Res. 2004 Mar;28(3):374-84
references.pmid: 15084894
references.citation: Genetics. 2007 Feb;175(2):917-22
references.pmid: 17179078
references.citation: Proc Natl Acad Sci U S A. 1984 Jan;81(1):258-61
references.pmid: 6582480
references.citation: PLoS Med. 2009 Mar 24;6(3):e50
references.pmid: 19320537
references.citation: Rev Clin Esp. 2005 Nov;205(11):528-32
references.pmid: 16324524
references.citation: J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S82-6
references.pmid: 18336671
references.citation: Adv Genet. 2008;60:311-34
references.pmid: 18358326
references.citation: Alcohol Clin Exp Res. 2008 May;32(5):785-95
references.pmid: 18331377
references.citation: Mol Psychiatry. 2007 Jan;12(1):47-54
references.pmid: 16969368
references.citation: J Med Genet. 1996 Feb;33(2):113-5
references.pmid: 8929946
references.citation: J Korean Med Sci. 2001 Dec;16(6):745-50
references.pmid: 11748356
references.citation: Arch Gen Psychiatry. 2007 Nov;64(11):1313-20
references.pmid: 17984400
references.citation: Stat Appl Genet Mol Biol. 2010;9:Article21
references.pmid: 20597847
references.citation: Neuropsychobiology. 2006;53(3):137-41
references.pmid: 16679777
references.citation: Am J Hum Genet. 1991 Apr;48(4):677-81
references.pmid: 2014795
references.citation: Alcohol Clin Exp Res. 1994 Jun;18(3):640-3
references.pmid: 7943668
references.citation: Hum Mol Genet. 2008 Mar 15;17(6):854-8
references.pmid: 18056758
references.citation: Psychiatry Clin Neurosci. 1999 Jun;53(3):397-405
references.pmid: 10459742
references.citation: Am J Med Genet. 1996 Jul 26;67(4):412-4
references.pmid: 8837712
references.citation: Gastroenterology. 2009 Nov;137(5):1768-75
references.pmid: 19698717
references.citation: Br J Psychiatry. 1996 Jun;168(6):762-7
references.pmid: 8773821
references.citation: Alcohol Clin Exp Res. 1997 Oct;21(7):1272-7
references.pmid: 9347089
references.citation: Eur J Epidemiol. 2008;23(5):323-6
references.pmid: 18404407
references.citation: Psychol Bull. 2006 Jul;132(4):607-21
references.pmid: 16822169
references.citation: Alcohol Clin Exp Res. 1999 Jun;23(6):958-62
references.pmid: 10397278
references.citation: Am J Hum Genet. 1999 Sep;65(3):795-807
references.pmid: 10441588
references.citation: Mol Biol Evol. 1995 Sep;12(5):921-7
references.pmid: 7476138
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Subst Use Misuse. 2010;45(1-2):1-14
references.pmid: 20025435
references.citation: Genet Med. 2007 Jan;9(1):4-8
references.pmid: 17224684
references.citation: Int J Epidemiol. 2005 Dec;34(6):1319-28
references.pmid: 16115824
references.citation: J Hepatol. 1995 Nov;23(5):519-23
references.pmid: 8583138
references.citation: Semin Liver Dis. 1988 Feb;8(1):12-25
references.pmid: 3283941
references.citation: Alcohol Res Health. 2007;30(1):5-13
references.pmid: 17718394
references.citation: Alcohol Clin Exp Res. 2011 Feb;35(2):304-16
references.pmid: 21083667
references.citation: Alcohol Clin Exp Res. 1996 Feb;20(1):52-5
references.pmid: 8651462
references.citation: Alcohol Alcohol. 2003 Sep-Oct;38(5):431-6
references.pmid: 12915519
references.citation: Genet Epidemiol. 2005 Feb;28(2):123-37
references.pmid: 15593093
references.citation: Proc Nutr Soc. 2004 Feb;63(1):49-63
references.pmid: 15099407
references.citation: Alcohol Clin Exp Res. 2009 Jun;33(6):985-90
references.pmid: 19302089
references.citation: Am J Psychiatry. 1995 Aug;152(8):1219-21
references.pmid: 7625477
references.citation: Alcohol Clin Exp Res. 2004 Aug;28(8):1145-52
references.pmid: 15318112
references.citation: Alcohol Clin Exp Res. 1995 Jun;19(3):564-6
references.pmid: 7573775
references.citation: Mol Psychiatry. 1999 Jan;4(1):85-8
references.pmid: 10089015
references.citation: Hepatology. 1996 Feb;23(2):234-9
references.pmid: 8591846
references.citation: Am J Gastroenterol. 2000 Oct;95(10):2958-64
references.pmid: 11051375
references.citation: Nat Genet. 2010 Mar;42(3):210-5
references.pmid: 20139978
references.citation: Nat Genet. 2011 Jun;43(6):531-8
references.pmid: 21572416
references.citation: Biol Psychiatry. 1997 Mar 15;41(6):703-9
references.pmid: 9066994
references.citation: Alcohol Clin Exp Res. 1995 Aug;19(4):951-4
references.pmid: 7485844
references.citation: Hepatology. 1994 Feb;19(2):360-6
references.pmid: 7904979
references.citation: Hum Mol Genet. 2006 Jun 15;15(12):1995-2002
references.pmid: 16687441
references.citation: Am J Psychiatry. 2005 May;162(5):1003-5
references.pmid: 15863807
references.citation: Lancet. 1994 Mar 19;343(8899):741-2
references.pmid: 7907720
references.citation: Ann Hum Genet. 1955 Jun;19(4):251-3
references.pmid: 14388528
references.citation: Neurosci Lett. 2007 Jan 29;412(2):139-42
references.pmid: 17196743
references.citation: PLoS Genet. 2011 Mar;7(3):e1001333
references.pmid: 21437268
references.citation: J Clin Epidemiol. 2008 Jul;61(7):634-45
references.pmid: 18538260
references.citation: Int J Geriatr Psychiatry. 2010 May;25(5):441-8
references.pmid: 19637400
references.citation: Arch Oral Biol. 1993 Sep;38(9):729-35
references.pmid: 8240079
references.citation: Arch Gen Psychiatry. 2004 Feb;61(2):184-91
references.pmid: 14757595
references.citation: Alcohol Clin Exp Res. 1999 Apr;23(4):592-9
references.pmid: 10235293