SummaryMitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2 * 504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2 * 504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2 * 504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2 * 504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2 * 504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2 * 504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2 * 504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.

We have analyzed the 5Ј-upstream promoter region of the presenilin 2 gene (PSEN2) for regulatory elements and examined Alzheimer disease (AD) patients and non-demented individuals for polymorphisms in the 5Ј upstream promoter region of the PSEN2 gene. Direct sequencing analysis detected a common single adenine (A) nucleotide deletion polymorphism in the upstream promoter region of the PSEN2 gene. Examination of cohorts of AD patients and agematched control individuals revealed no statistically significant differences in the frequency of this polymorphism when compared with the total sample of AD patients and control individuals. However, subgroup and regression analysis suggested that the relatively rare −A/−A genotype increases risk of AD among subjects lacking apolipoprotein E (APOE) ⑀4 and among persons ages 65 years and younger. DNA sequence and DNA-protein binding analysis demonstrated that this mutation negates binding with putative repressor transcription factor (TF), interferon regulatory factor 2 (IRF2), in nuclear extracts prepared from the aged human brain neocortex. However this mutation creates a potential regulatory element, C/EBPbeta, that is responsive to pro-inflammatory (PI) induction. The expression activity assay with luciferase reporter gene into normal human neural progenitor cells in primary culture shows that the mutant PSEN2 regulatory region exhibits a 1.8-fold higher level of basal expression and is sensitive to IL−1␤ and A␤42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL−1␤+A␤42]. These results suggest that under Pl and oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that consequently these may play a role in the induction and/or proliferation of a Pl response in AD brain.