Amyloid-β-Related Genes SORL1 and ACE are Genetically Associated With Risk for Late-onset Alzheimer Disease in the Chinese Population

Late-onset Alzheimer Disease (LOAD) is a common neurodegenerative disease, and one of its major pathologic characteristics is senile plaques. Proteins encoded by SORL1 and ACE have been shown to be related to the processing, trafficking, and degradation of Amyloid-beta, the principal component of senile plaques. In this paper, we investigated whether SORL1 and ACE are associated with LOAD. We recruited 144 LOAD patients and 476 controls from Shanghai, China and conducted a case-control study on 9 single-nucleotide polymorphisms (SNPs): 6 in SORL1 (rs2070045, rs661057, rs668387, rs689021, rs3824968, rs2282649) and 3 in ACE (rs1800764, rs4343, rs1799752). Despite the small case sample size (144), we observed that rs1800764, rs4343, rs1799752 in ACE, and rs2070045, rs3824968, rs2282649 in SORL1 showed significantly different allele frequencies between patients and controls (P = 4.57 x 10(-2), 5.24 x 10(-3), 1.95 x 10(-4), 1.77 x 10(-4), 6.44 x 10(-3), and 3.11 x 10(-3), respectively). Moreover, haplotypes on ACE and on SORL1 were significantly associated with LOAD (all P-value < 0.009 in ACE and all P-value < 0.003 in SORL1). In ACE, we found the most significant protective haplotype encompasses SNPs rs2070045, rs3824968, and rs2282649 (C-G-D: OR = 0.20, P = 8.96 x 10(-14)). In SORL1, we detected a "complementary" haplotype (G-A-T: OR = 1.54, P = 2.67 x 10(-3); T-T-C: OR = 0.63, P = 2.36 x 10(-3)) composed of SNPs rs2070045, rs3824968, and rs2282649. In addition, we carried out meta-analysis with 3 other Asian populations on 3 SNPs in SORL1 (rs2070045, rs3824968, and rs2282649). Results supported our initial finding that these 3 SNPs were associated with LOAD. Our data suggested that SORL1 and ACE might play a role in LOAD susceptibility among Han Chinese.