It is noteworthy that it is risk for, rather than resistance to, the development of dependence that has been targeted in most research. Resistance-enhancing effects, if any reported, are either defined by an allele’s virtue of being the alternative to the “risk” allele, or noted inadvertently, as, for instance, the detection of the “protective” effect of the minor allele of the rs16969968 SNP of the CHRNA5 gene (a “risk” allele for nicotine dependence) on the risk for cocaine dependence (Grucza et al., 2008). The largest addiction-related genetic effect, however, has been established when a phenotypic resistance factor was specifically targeted. A higher sensitivity to ethanol (“flushing” upon exposure) among East Asians (particularly, the Japanese) was established by comparison with Caucasians (Wolff, 1972) and subsequently experimentally related to a higher level of acetaldehyde upon exposure to ethanol (Wolff, 1973). Flushing among the Japanese was then related to the “atypical” form of acetaldehyde dehydrogenase deficiency (Harada, Agarwal, & Goedde, 1981) and, finally, to the ALDH2*2 allele of the gene coding for the β2 subunit of the enzyme (Goedde, Agarwal, & Harada, 1983).
