RESEARCH genotype has been found to be present in 6 – 17 per cent of alcohol-dependent subjects, compared with 30 – 45 per cent of non-alcoholic subjects.5,33,34 This difference in ALDH2*2 allele frequency between alcoholic and non-alcoholic subjects has been postulated to be responsible for the phenom- enon of adverse responses to alcohol consumption, such as facial ﬂushing, nausea and tachycardia in individuals with the inactive form of the enzyme.29 In contrast to the reports from the neighbouring East Asian population, the present study found comparatively higher allele (ALDH2*2 ¼ 0.19) and genotypic (ALDH2*2/*2 ¼ 0.11, ALDH2*1/*2 ¼ 0.16) frequencies in alcohol-dependent individuals. A recent study28 from India is equally exciting, however, as it found the SNP to be monomorphic (ALDH2*1/2*1) in healthy control subjects. In light of the ﬁndings of that recent report,28 as well as that of Goedde et al.,35 the higher frequency of the inactive ALDH2 allele observed in our Indian alcohol-dependent subjects, compared with the control population, provides evidence for a direct role of acetaldehyde in the development of alcohol addiction (despite its toxic actions). Further, the amount of alcohol consumed by ALDH2*2/*2 individuals is signiﬁcantly lower than those with ALDH2*1/*1 and ALDH2*1/*2 genotypes (Table 1). It should be noted that, although subjects with the ALDH2*2/*2 genotype in this study are classiﬁed as alcohol dependent by DSM IV criteria, these individuals are only drinking three to ﬁve res- taurant glasses per day (of Indian liquor, with 8 g alcohol/drink), which is not enough to produce ethanol intoxication, but rather acetaldehyde intoxi- cation. When we compared our ﬁndings in alcohol- dependent subjects with those of an Indian control population (see Bhaskar et al.28), our ﬁndings were in concurrence with those of Hahn et al.,36 where the pleasurable effects of acetaldehyde led to higher positive expectancies in individuals with the ALDH2*1/*2 compared with the ALDH2*1/*1 genotype. As suggested by Chen et al.,37 the plea- surable effects of acetaldehyde leading to higher positive expectancies in individuals with the ALDH2*1/*2 compared with the ALDH2*1/*1 genotype could be due to a development of Vaswani, Prasad and Kapur tolerance to acetaldehyde. The present observation of the development of AD (in ALDH2*2/*2 indi- viduals) with low levels of alcohol consumption but with presumably high levels of acetaldehyde strongly implicates acetaldehyde in the causality of the dependence. The above conclusion might be weakened/challenged, however, by a comparison of our data on AD subjects with an analysis involving ethnicity, age and sex-matched controls; this is cur- rently ongoing in our laboratory. Two clinical parameters — namely, duration of AD and age at onset of AD — 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 geno- type, 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 con- sumption among ALDH2*1/*1 subjects. Our ﬁndings indicate that functional poly- morphism of the gene coding for the ALDH enzyme affects the propensity to develop AD. The most important ﬁnding of the study was the 218 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 3. NO. 3. 213–220 APRIL 2009