Association between promoter polymorphisms in anterior pharynx-defective-1a and sporadic Alzheimer's disease in the North Chinese Han population.

Amyloid beta-peptide (Abeta) deposition in brain is important in the development of sporadic Alzheimer's disease (SAD) and Abeta is produced through sequential cleaving of amyloid precursor protein (APP) by beta-secretase and gamma-secrease. Anterior pharynx-defective-1 (APH-1) is an important subunit of the gamma-secretase complex, and its expression level was associated with the activity of gamma-secrease. We hypothesized that alterations in the APH-1 promoter region might alter APH-1 expression and the activity of gamma-secrease, thus be involved in the SAD process. In the present study, we sequenced APH-1a promoter region in 20 randomly selected controls and 20 SAD patients and detected two polymorphisms which were -980C/G (rs3754048) and -21C/A (rs2275780). Then, we investigated genotypes and allele of these two polymorphisms as well as apolipoprotein epsilon4 (APOE epsilon4) status in 256 SAD patients and 276 normal controls with restriction fragment length polymorphisms analysis and sequencing. Results showed the GG genotype and G allele of -980C/G polymorphism were more frequent in the SAD group than that in the controls not only in the whole subjects (genotype P=0.038, allele P=0.01 respectively) but also in the APOE epsilon4+subjects (genotype P=0.048, allele P=0.016 respectively). There was no statistical difference between SAD group and controls regarding to the frequency of alleles and genotypes of -21C/A whenever before or after stratification by APOE epsilon4. Our results suggest that there is an association between -980C/G and the development of SAD in the Northern Han Chinese population and that allele G may interact synergistically with the APOE epsilon4 allele to increase the risk of SAD.