Association of ADH1B and ALDH2 gene polymorphisms with alcohol dependence RESEARCH with the ALDH2*1/2*1 and 29 per cent of those with the ALDH2*1/*2 genotype drank almost every day. Subjects drinking excessive amounts (.60 g/day), however, were more likely to have the ALDH2*1/*1 or the ALDH2*1/*2 genotype than the ALDH2*2/*2 genotype. Discussion and conclusion The pharmacokinetics of ethanol metabolism inﬂu- ences the risk for AD. Although the role of ADH1B and ALDH2 genes in susceptibility to alcoholism were discovered individually, they have been shown to act additively when they co-occur. The ADH1B*2 and ALDH2*2 alleles raise the levels of acetaldehyde by increasing the rate of syn- thesis and decreasing the rate of metabolism respectively, thus interacting additively but not synergistically. At the protein level, the allelic series for ADH1B is generated by variation at two different sites at the genomic level. The ADH1B*1 allele is composed of 47Arg and 369Arg; the ADH1B*2 allele is com- posed of 47His and 369Arg; and the ADH1B*3 allele is composed of 47Arg and 369Cys. Caucasians are largely monomorphic for the ADH1B*1 allele,25 with a very low frequency of the ALDH2*2 allele. The ADH1B*2 allele, which is known to confer protection against alcoholism and is relatively common in East Asian popu- lations,21 was found to be present at very low fre- quency (,0.001) in our study. Our observation is similar to that reported by Reddy et al.24 in tribal populations from southern India. Since the ADH1B*3 (ADH1B*369Cys) allele has been documented to be essentially speciﬁc to the African population, we did not genotype ADH1B*3 in our study population.24 Although consistent with the recent report by Reddy et al.,24 the very low frequency of the ADH1B*2 allele found in our population is sur- prising, since it is present at a substantial frequency in the neighbouring East Asian population and confers protection against alcoholism. A very low frequency of ADH1B*2 could indicate a selection pressure operating against the ADH1B*2 allele in our population due to its inability/redundancy to protect the Indian population from AD. Commenting on the alcohol-consuming practice of the service/working and lower caste of Indian society, Reddy et al.24 suggested that, due to the heavy amount of alcohol consumption on a regular basis, most of these subjects might have developed a genetic adaptation to withstand drinking alcohol (unlike most East Asian populations with known sensitivity to alcohol consumption), thereby poss- ibly requiring no protective mechanism and hence resulting in the absence of the ADH1B*2 allele. The present study was conducted at a government facility, where treatment is available free of charge and is accessed mainly by people from low income strata belonging to the working class of Indian society. It is well known that socio-economically underprivileged groups consume alcohol for mental and physical relaxation. Therefore, the explanation given by Reddy et al.24 could also support a very low frequency of the ADH1B*2 allele in the present study. A stronger inﬂuence of social setting and age than the effect of the ADH1B*2 allele on alcohol drinking has also been found in a study in a Jewish population,32 which supports the above-mentioned hypothesis of an environmental inﬂuence on genetic constitution with regard to the ADH1B gene in the Indian population. The ALDH2 gene is located on chromosome 12q24. The single bp difference (G . A; Glu487Lys) in exon 12 causes the normal allele, ALDH2*1, to become a non-functional (ALDH2*2) allele, which codes for the inactive enzyme.6 The ALDH2*2 allele, which is prevalent in Asian populations but is extremely rare in non-Asians, has the strongest protective association with AD. Asian subjects homozygous for ALDH2*2 have an almost zero risk of developing AD, whereas heterozygotes (ALDH2*1/2*2) are about one-third as likely to be alcoholic, compared with those without this allele.14 Assanangkornchai et al.29 reported that the homozygous ALDH2*2/*2 genotype is present at a very low frequency (0 – 0.3 per cent) in alcoholic patients, compared with 3 – 12 per cent among non- alcoholic subjects. The heterozygous ALDH2*1/*2 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 3. NO 3. 213–220 APRIL 2009 217