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We investigated insertion (Ins)/deletion(Del) polymorphism in alpha-2-macroglobulin (A2M), G/C variant in the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and apolipoprotein E (APOE) gene epsilon2/epsilon3/epsilon4 polymorphism in 387 Chinese Han ethnic patients with Alzheimer's disease and healthy study participants. After stratification for APOEepsilon4 status, only the BACE1-G allele with APOEepsilon4 was significantly associated with Alzheimer's disease. Through meta-analysis of the Del or G allele by pooling Asian studies, only BACE1-G allele appeared to increase risk of developing Alzheimer's disease. Through combination-analysis of the data about the A2M-I/D and the A2M-Ile1000Val variants, the A2M gene was suggested to be associated with Alzheimer's disease.

Beta-site amyloid-precursor protein cleaving enzyme (BACE1) is a candidate risk factor for Alzheimer's disease (AD) because of involving in generating beta-amyloid peptide, which is thought to play a central role in the pathogenesis of the disease. A single nucleotide polymorphism 1239G/C in exon 5 of BACE1 gene and a weak association between this polymorphism and AD in Caucasian APOEepsilon4 allele carriers has been reported. To examine possible association of the polymorphism with sporadic AD, two Chinese Han cohorts including 257 patients and 242 age-matched controls in Guangzhou and 112 patients and 113 controls in Chengdu were genotyped using PCR-RFLP techniques. The frequency of the C allele in controls of both cohorts was 0.65, which was higher than that in Caucasian populations [0.39 by Nowotny et al. 2001: Neuroport 12:1799-1802; 0.44 by Nicolaou et al. 2001: Neurogenetics 3:203-206]. There was a significant excess of C allele among the patients in both cohorts (Guangzhou, 0.71 vs. 0.65, chi(2) = 5.20, P = 0.02; Chengdu, 0.74 vs. 0.65, chi(2) = 4.36, P = 0.04). The CC genotype was found to be associated with AD (Guangzhou cohort, OR = 1.56, 95% CI = 1.09-2.23; Chengdu cohort, OR = 1.74, 95% CI = 1.03-2.95; combined sample: OR = 1.61, 95% CI = 1.20-2.17). The association remained in non-APOE epsilon4 allele carriers when all subjects were divided on the basis of the APOEepsilon4 status. Our findings suggest that the 1239G/C polymorphism in exon 5 of BACE1 gene may be associated with sporadic AD in Chinese Hans., (Copyright 2003 Wiley-Liss, Inc.)