The present study shows the occurrence of the minor alleles of rs671 and rs698 at a frequency between 21-30% and 33-38% respectively in the south Indian study population. The frequency of rs671 across Asian populations (19% Japanese, 23 % Chinese, 36% Koreans) is quite similar to the frequencies observed in this south Indian population. Among Indian populations, intriguingly a study reported Glu504 to be monomorphic in some Indian populations (Madhya Pradesh, Maharashtra and Andhra Pradesh)  in healthy controls. However, Vaswani et al. found the ALDH2*2 minor allele to be present at a frequency of 19% in a north Indian population which agrees with the finding of the present study .The minor allele frequency of rs698 in this study population is marginally higher than north Indians (25%) and south West Indians (27%) [14,30]. Across the major global populations, the frequency of this allele is seen at 50% in Caucasians and 15% in African Americans  and is the least frequent in east Asians [16,31].
The present study found a significant rs671 allelic association with AD which was also reflected in the dominant genetic model. The strong protective effect of ALDH2*2 against AD is well-established. A meta-analysis showed a very strong association of rs671 with alcohol dependence and alcohol abuse with an allelic p value of 3x10-56. The study also showed significance with dominant model (lys-lys + lys-glu vs. glu-glu) concurring with the findings of the present study. The significant association between the decreased risk of alcohol dependence and ALDH2*2 has been shown in many Asian studies [23,26] including a meta-analysis that demonstrated the link between ALDH2*1 and increased risk of AD according to a dominant model only in east Asians. O’Shea et al. analyzed the relationship between ALDH2*2 A allele and peer drinking in east Asian college students confirming the strong protective effect of ALDH2*2 against alcohol addiction . In an Indian study though, in contrast to studies on Asian subjects, Vaswani et al. found a high frequency of ALDH2*2 among north Indian alcohol dependent subjects and deemed it to be a risk factor. However, the amount of alcohol consumption in rs671 homozygous mutants was significantly lower compared to other genotypes .
More recently, a GWAS (including a discovery and replication cohort) in Han Chinese alcoholic dependents and controls and in their analysis of polygenic risk scores (PRS) derived from GWAS summary statistics with European American, African American and Thai population revealed the significant association of ALDH2 rs671 and ADH1B rs1229984 with AD . In a family-based association test in Taiwanese subjects followed by case-control study and a meta-analysis of both studies, rs671, rs698 and rs1229984 were significantly associated with AD among 282 SNPs and 61 genes involved in the systems of dopamine, serotonin, GABA, and alcohol metabolism . Our study did not find any association between rs698 and AD. The combination of risk and protective alleles from rs671 and rs698 also showed no association with AD.
In an earlier Indian study that reported a considerable frequency of rs698 (about 35%) in north Indian population, no association was found between rs698 and alcoholism . Borras et al., also reported no association between AD and ADH1C*1 in European individuals . These reports are contradictory to many studies across major global populations where ADH1C*1, Ile350 has been shown to lower the risk of AD . The protective effect Ile350 is consistently reported in different Asian populations [18,36] than in non-Asian populations [24,37–39] However, in a Turkish study, rs698 was not associated with AD whereas rs1229984 (Arg47His, also referred to as ADH1B*2) which is in high linkage disequilibrium with rs698 was associated with AD . rs1229984 is also highly prevalent in Asian population but is rarely seen in non-Asians [6,15,41]. rs1229984 is linked with the pathogenesis of alcohol dependence  and is protective against AD in different populations [22,42–44].This functional variant encodes β2β2, a more active form of the enzyme that results in rapid oxidation of ethanol and higher concentrations of acetaldehyde [45,46]. It has been suggested that the protective effect of ADH1C*1 could be in part attributed to its strong LD with ADH1B*2 . rs698 and the second allelic variant of ADH1C*2 rs1693482 were also found to be in high LD with rs1789891 which is significantly associated with AD and is located between ADH1B and ADH1C . There was significant association between ADH1B rs129984 and ADH1C rs698, rs1693482 variants as well as ADH1C-1B intergenic markers and alcohol dependence syndrome in British and Irish population .
The variants of the ADH cluster are in strong LD with each other to an extent that precludes the analysis of independent effect of these variants . Since the ADH1 genes are in close proximity with each other, different variants in each of these genes could influence alcoholic behavior. The analysis of joint effect of ADH1C and ADH1B variants is warranted in future studies .
In a study that analyzed the effect of ADH variants alongside religious involvement, rs698 was associated with higher maximum drinks and more alcohol dependence symptoms with low or no religious involvement but not with higher religious involvement levels , suggesting the significant influence of social factors in modifying the genetic susceptibility. The results of the present study also show the significant influence of social and environmental factors such as family history of AD and level of education in modulating the risk of AD while diminishing the significance of genetic factors in influencing the susceptibility to AD.