The review of candidate gene studies revealed a number of polymorphisms that have been found to be associated with substance dependence phenotypes in Native Americans. The strongest results were reported from studies investigating the genes that code for alcohol metabolizing enzymes, including variants in ADH1B (rs1229984 and rs2066702) and ADH4 (rs3762849). Notably, these results were not always consistent across tribal groups. Some of these differences may be the result of population differences such as the observed association of the ADH1B*3 allele (rs2066702) in the California Indian sample and the absence of this allele in the other tribal groups examined. Others, such as the ADH1B*2 allele (rs1229984) and rs3762849 in ADH4 were more likely the result of inadequate sample sizes given that the direction of effect was consistent across studies. Larger studies including a greater number of tribal groups will be needed to conclusively test these conclusions. Thus far, the reviewed studies suggest that some Native American tribes appear to lack protective variants in alcohol metabolizing enzyme genes that are seen in East Asian and some African population groups (e.g., ALDH2*2
