RESEARCH predisposing to AD have been carried out in several Western, African, Jewish, Korean, Japanese and Chinese populations.14,15 Although India rep- resents about one-sixth of the world’s population, there are very few data on genes/polymorphisms that confer susceptibility to AD in this population. Genetic polymorphisms, particularly those of the alcohol metabolising enzymes alcohol dehydrogen- ase (ADH) and aldehyde dehydrogenase (ALDH), have been largely implicated in the development of AD.16 – 18 In order to identify speciﬁc genes affect- ing vulnerability or resistance, Long et al.16 per- formed a whole-autosomal genome scan for genetic linkage to AD in a Southwestern American Indian tribe. A highly suggestive piece of evidence for the linkage of three loci in the ADH gene cluster on chromosome 4q was observed. These ﬁndings were conﬁrmed by the Collaborative Study on the Genetics of Alcoholism (COGA) study.17 On the basis of the genotype frequencies of ADH1B and ALDH2 polymorphisms, the risk for alcoholism in the Japanese population was accu- rately estimated by Higuchi et al.19 They concluded that the Japanese population may be protected from alcoholism by inactive ALDH2 and higher frequen- cies of atypical ADH1B. Functional polymorphisms in the genes encoding these enzymes inﬂuence the rate of synthesis and metabolism of acetaldehyde, the toxic metabolite of ethanol. The presence/absence of these polymorph- isms in the population could modulate the prob- ability of the development and relapse of AD, and confer protection/susceptibility to alcohol abuse and alcohol-related complications. The most widely studied functional polymorphisms in the ethanol metabolic pathway are the ADH1B Arg47His and ALDH2 Glu487Lys polymorphisms.20 The ADH1B*2 (ADH1B*47His) allele codes for a higher activity enzyme as compared with the ADH1B*1 (ADH1B*47Arg) allele21,22 and is thus known to inﬂuence drinking behaviour, resulting in protection from alcoholism. Chen et al.,23 in a case control analysis, found that individuals carrying one or two copies of the ADH1B*2 allele and a single copy of ALDH2*2 had the lowest risk (odds ratios 0.04 – 0.05) for alcoholism, as compared with Vaswani, Prasad and Kapur the ADH1B*1/*1 and ALDH2*1/*1 genotype. Further, the authors concluded that the disease risk associated with the ADH1B*2/*2 – ALDH2*1/*1 genotype is about half of that associated with the ADH1B*1/*2 – ALDH2*1/*1 genotype. Their result suggests that the protection afforded by the ADH1B*2 allele may be independent of that afforded by ALDH2. A considerable variation in the allele frequency of this polymorphism has been observed among different ethnic groups.22 The ADH1B*2 allele is found to be more common in non-alcoholic than in alcoholic groups in popu- lations from East Asia, Taiwan, Spain, New Zealand and in Jews from Israel and the USA. Due to the very low frequency of the ADH1B*2 allele in the Caucasian population, however, associ- ation studies have mostly remained inconclusive.24 Reports on the ADH1B*2 allele (Arg47His poly- morphism) frequency in the Indian population are inconsistent. Goedde et al.25 reported a 9.9 per cent ADH1B*2 allele frequency in a heterogeneous sample from the Indian population, whereas another study from India (on the Kachari popu- lation) reported a 6.6 per cent frequency.21 Recently, in a robust study involving 28 Indian tribal populations, the polymorphism has been found to be monomorphic (ADH1B*1/*1), with complete absence of the ADH1B*2 allele.24 Based on their ﬁndings, those authors argued that Indians (mainly those comprising the lower caste and working class) could have developed tolerance to the adverse effects of alcohol, and thus the protection-conferring ADH1B*2 allele has been selected out from the population. Mitochondrial ALDH2 plays a major role in ethanol metabolism. It is involved in the oxidation of acetaldehyde to acetate. Sensitivity to ethanol is highly associated with a functional polymorphism, Glu487Lys, and the 487Lys (ALDH2*2) allele is responsible for a deﬁciency in ALDH2 activity.26 High concentrations of acetaldehyde, due to the presence of the ALDH2*2 allele, lead to adverse reactions to alcohol,27 which reduce the probability of heavy drinking vis-a`-vis AD and other alcohol- related problems. Clinical and pharmacokinetic studies have indicated that individuals who show 214 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 3. NO. 3. 213–220 APRIL 2009