Worldwide, the most robust finding for genetic influences on AUD is for genes encoding ethanol metabolizing enzymes. Ethanol is largely metabolized in the liver by alcohol dehydrogenases (ADH) to toxic acetaldehyde which is then converted to acetate by aldehyde dehydrogenases (ALDH), primarily by the mitochondrial enzyme ALDH2. Since functional variants in these genes have a high prevalence in East Asians and some studies have suggested East Asian ancestry for the original Native Americans, these variants have been investigated in AI/AN. The ALDH2*2 allele, encoding the inactive ALHD2 enzyme which results in a severe flushing syndrome upon ethanol consumption, has not been found in Plains American Indians, Southwestern American Indians and Southwest California Indians42,43 and indeed appears to be unique to East Asians.
