Association of ADHIB and ALDH2gene polymorphisms with alcohol dependence: A pilot study from India

Abstract

Functional polymorphism in the genes encoding alcohol dehydrogenase (ADH) 1B and aldehyde dehydrogenase (ALDH) 2 are considered most important among several genetic determinants of alcohol dependence, a complex disorder. There is no report on the widely studied Arg47His and Glu487Lys polymorphisms from Indian alcoholdependent populations. In this paper, we report, for the first time, allelic and genotypic frequencies of Arg47His and Glu487Lys single nucleotide polymorphisms (SNPs) in North Indian alcohol-dependent subjects. A total of 174 alcohol-dependent males, recruited using DSM IV criteria (American Psychiatric Association, 1994), were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. The results obtained from genetic analysis were correlated with clinical parameters using Student's t-test or Mann Whitney's U test. The highlight of the study findings was the uniquely high frequency of the ALDH2*2/*2 genotype (among alcohol-dependent subjects) being a risk-conferring factor for alcohol dependence.

correlated well with the protection-conferring property of the ALDH2 Glu487Lys polymorphism. The duration of AD was found to be significantly longer (p < 0.01) among individuals with the ALDH2*1/*1 genotype, compared with ALDH2*2/*2 subjects. The age at which patients developed AD, however, was significantly lower (p < 0.01) in individuals with the ALDH2*1/*1 genotype compared with ALDH2*2/*2 subjects (Table 1). Alcohol-induced flushing is inherited as a dominant trait in Asians [38]. A substantial number of Asians (50-80 per cent), compared with Caucasians (3-12 per cent), exhibit flushing [39, 40]. Acetaldehyde creates unpleasant adverse reactions by acting as a major deterrent to excessive alcohol drinking on the one hand, while giving the euphoric sensations that may reinforce alcohol drinking on the other [41].

Since people with the inactive ALDH2*2 allele drink less often and consume less alcohol per occasion than those with the active ALDH2*1 allele, our observation of a significantly lower age at onset and longer duration of AD among individuals with the ALDH2*1/*1 genotype compared with those with the ALDH2*2/*2 genotype seems to be in keeping with the available literature. Significantly higher values of SGOT and SGPT in individuals with the ALDH2*1/*1 genotype, compared with the ALDH2*2/*2 genotype (Table 1), is suggestive of more liver damage due to higher alcohol consumption among ALDH2*1/*1 subjects.

Our findings indicate that functional polymorphism of the gene coding for the ALDH enzyme affects the propensity to develop AD. The most important finding of the study was the uniquely high frequency of the ALDH2*2/*2 genotype (among alcohol-dependent subjects) being a risk-conferring factor for AD. Further, based on the findings from this study, albeit based on a limited sample size, it could be hypothesised that the Indian genotype is prone to slow metabolism of alcohol and high metabolism of acetaldehyde, and thereby prone to alcoholism. Our findings should be viewed, however, in the perspective of the potential limitation posed by the absence of data from an ethnically, age- and sex-matched control population. Further, these results not only warrant replication in larger sample sets, but also underscore the need for investigations on candidate gene polymorphisms from other biochemical pathways.

Declarations

Acknowledgments

The authors acknowledge the constructive suggestions from Dr Atul Ambekar, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India.

References

Heinz A, Goldman D, Gallinat J, et al: Pharmacogenetic insights to monoaminergic dysfunction in alcohol dependence. Psychopharmacology (Bert). 2004, 174: 561-570.Google Scholar

Schuckit MA: Alcohol-related disorders. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Edited by: Sadock, BJ, Sadock, VA, Kaplan, HI. 2004, Lippincott Williams & Wilkins, Philadelphia, PA, USA, 8Google Scholar

Schramm-Sapyta NL, Kingsley MA, Rezvani AH, et al: Early ethanol consumption predicts relapse-like behavior in adolescent male rats. Alcohol Clin Exp Res. 2008, 32: 754-762. 10.1111/j.1530-0277.2008.00631.x.Google Scholar

Reich T, Edenberg HJ, Goate A, et al: Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet. 1998, 81: 207-215. 10.1002/(SICI)1096-8628(19980508)81:3<207::AID-AJMG1>3.0.CO;2-T.Google Scholar

Thomasson HR, Edenberg HJ, Crabb DW, et al: Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet. 1991, 48: 677-681.Google Scholar

Yoshida A, Hsu LC, Yasunami M: Genetics of human alcohol-metabolizing enzymes. Prog Nucleic Acid Res Mol Biol. 1991, 40: 255-287.Google Scholar

Bosron WF, Ehrig T, Li TK: Genetic factors in alcohol metabolism and alcoholism. Semin Liver Dis. 1993, 13: 126-135. 10.1055/s-2007-1007344.Google Scholar

Chen WJ, Loh EW, Hsu YP, et al: Alcohol-metabolizing genes and alcoholism among Taiwanese Han men: Independent effect of ADH1B, ADH3, and ALDH2. Br J Psychiatry. 1996, 168: 762-767. 10.1192/bjp.168.6.762.Google Scholar

Tanaka F, Shiratori Y, Yokosuka O, et al: Polymorphisms of alcohol metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men. Alcohol Clin Exp Res. 1997, 21: 596-601. 10.1111/j.1530-0277.1997.tb03808.x.Google Scholar

Li TK: Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol. 2000, 61: 5-12.Google Scholar

US Department of Health and Human Services (HHS.gov) The substance abuse and mental health services administration (SAMHSA): Underage Alcohol Use: Findings from the 2002-2006 National Surveys on Drug Use and Health. 2006Google Scholar

Ray R: Ministry of Social Justice and Empowerment, Government of India and United Nations Office on Drugs and Crime. The Extent, Pattern and Trends of Drug Abuse in India: National Survey. 2004, New Delhi, IndiaGoogle Scholar

Tu GC, Israel Y: Alcohol consumption by Orientals in North America is predicted largely by a single gene. Behav Genet. 1995, 25: 59-65. 10.1007/BF02197242.Google Scholar

Wall TL, Carr LG, Ehlers CL: Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in Native American Mission Indians. Am J Psychiatry. 2003, 160: 41-46. 10.1176/appi.ajp.160.1.41.Google Scholar

Edenberg HJ, Xuei X, Chen HJ, et al: Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis. Hum Mol Genet. 2006, 15: 1539-1549. 10.1093/hmg/ddl073.Google Scholar

Long JC, Knowler WC, Hanson RL, et al: Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am J Med Genet. 1998, 81: 216-221. 10.1002/(SICI)1096-8628(19980508)81:3<216::AID-AJMG2>3.0.CO;2-U.Google Scholar

Saccone NL, Kwon JM, Corbett J, et al: A genome screen of maximum number of drinks as an alcoholism phenotype. Am J Med Genet. 2000, 96: 632-637. 10.1002/1096-8628(20001009)96:5<632::AID-AJMG8>3.0.CO;2-#.Google Scholar

Higuchi S, Matsushita S, Imazeki H, et al: Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet. 1994, 343: 741-742.Google Scholar

Higuchi S, Matsushita S, Murayama M, et al: Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. Am J Psychiatry. 1995, 152: 1219-1221.Google Scholar

Goldman D, Oroszi G, Ducci F: The genetics of addictions: uncovering the genes. Nat Rev Genet. 2005, 6: 521-532.Google Scholar

Osier MV, Pakstis AJ, Soodyall H, et al: A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am J Hum Genet. 2002, 71: 84-99. 10.1086/341290.Google Scholar

Whitfield JB: Alcohol dehydrogenase and alcohol dependence: Variation in genotype-associated risk between populations. Am J Hum Genet. 2002, 71: 1247-1250. 10.1086/344287.Google Scholar

Chen CC, Lu RB, Chen YC, et al: Interaction between the functional polymorphism of the alcohol metabolism genes in protection against alcoholism. Am J Hum Genet. 1999, 65: 795-807. 10.1086/302540.Google Scholar

Reddy BM, Reddy ANS, Nagaraja T, et al: Single nucleotide polymorphisms of the alcohol dehydrogenase genes among the 28 caste and tribal populations of India. Int J Hum Genet. 2006, 6: 309-316.Google Scholar

Goedde HW, Agarwal DP, Fritze G, et al: Distribution of ADH1B and ALDH2 genotypes in different populations. Hum Genet. 1992, 88: 344-346.Google Scholar

Ohta S, Ohsawa I, Kamino K, et al: Mitochondrial ALDH2 deficiency as an oxidative stress. Ann NY Acad Sci. 2004, 1011: 36-44. 10.1196/annals.1293.004.Google Scholar

Bosron WF, Lumeng L, Li TK: Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. Mol Aspects Med. 1988, 10: 147-158. 10.1016/0098-2997(88)90019-2.Google Scholar

Bhaskar LV, Thangaraj K, Osier M, et al: Single nucleotide polymorphisms of the ALDH2 gene in six Indian populations. Ann Hum Biol. 2007, 34: 607-619. 10.1080/03014460701581419.Google Scholar

Assanangkornchai S, Noi-pha K, Saunders JB, Ratanachaiyavong S: Aldehyde dehydrogenase 2 genotypes, alcohol flushing symptoms and drinking patterns in Thai men. Psychiatry Res. 2003, 118: 9-17. 10.1016/S0165-1781(03)00043-X.Google Scholar

Shen YC, Fan JH, Edenberg HJ, et al: Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res. 1997, 21: 1272-1277. 10.1111/j.1530-0277.1997.tb04448.x.Google Scholar

Lee DH, Ha MH, Christian DE: Body weight, alcohol consumption, and liver enzyme activity -- A 4 year follow up study. Int J Epidemiol. 2001, 30: 766-770. 10.1093/ije/30.4.766.Google Scholar

Carr LG, Foroud T, Stewart T, et al: Influence of ADH1B polymorphism on alcohol use and its subjective effects in a Jewish population. Am J Med Genet. 2002, 112: 138-143. 10.1002/ajmg.10674.Google Scholar

Chao YC, Liou SR, Chung YY, et al: Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients. Hepatology. 1994, 19: 360-366. 10.1002/hep.1840190214.Google Scholar

Higuchi S, Matsushita S, Muramatsu T, et al: Alcohol and aldehyde dehydrogenase genotypes and drinking behaviour in Japanese. Alcohol Clin Exp Res. 1996, 20: 493-497. 10.1111/j.1530-0277.1996.tb01080.x.Google Scholar

Goedde HW, Agarwal DP: Aldehyde oxidation: Ethnic variations in metabolism and response. Prog Clin Biol Res. 1986, 214: 113-138.Google Scholar

Hahn CY, Huang SY, Ko HC, et al: Acetaldehyde involvement in positive and negative alcohol expectancies in Han Chinese persons with alcoholism. Arch Gen Psychiatry. 2006, 63: 817-823. 10.1001/archpsyc.63.7.817.Google Scholar

Chen YC, Lu RB, Peng GS, et al: Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele. Alcohol Clin Exp Res. 1999, 23: 1853-1860. 10.1111/j.1530-0277.1999.tb04083.x.Google Scholar

Schwitters SY, Johnson RC, Johnson SB, Ahern FM: Familial resemblances in flushing following alcohol use. Behav Genet. 1982, 12: 349-352. 10.1007/BF01067854.Google Scholar

Schwitters SY, Johnson RC, McClearn GE, Wilson JR: Alcohol use and the flushing response in different racial groups. J Stud Alcohol. 1982, 43: 1259-1262.Google Scholar

Goedde HW, Agarwal DP: Polymorphism of aldehyde dehydrogenase and alcohol sensitivity. Enzyme. 1987, 37: 29-44.Google Scholar

Eriksson CJ: The role of acetaldehyde in the actions of alcohol (update 2000). Alcohol Clin Exp Res. 2001, 25 (5 Suppl. ISBRA): 15S-32S.Google Scholar