| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
SNP scanning at about 100 kb distance of late onset Alzheimer disease (LOAD) at chromosome 12p and 21 loci were performed, using 188 cases of the patients with LOAD and 375 population-based controls (The 1st stage). We identified disease-related effects in 73 SNPs (out of 389 SNPs,18.8%) at the 12p locus, and 59 SNPs (out of 456 SNPs,14.1%) at the 21 locus. In the 2nd stage, the confirmatory genotyping was done using 375 cases and the same 375 controls. In case of the chromosome l12p locus, 15 SNPs found by logistic regression, 2 SNPs found by haplotype risk effect, and 1 SNP found by age-at-onset correlation at the 1st stage (total 18 SNPs) were indicated significant linkage disequilibriums with LOAD. A risk locus spanning in the range of 300 kb (27.0-27.3 Mb from 12p-ter), harboring one gene relating to transcriptional regulation, coincided to the locus between D12S1042 (27.5 Mb from 12p-ter) and D12S1057 (24.6Mb from 12p-ter). In case of the chromosome 21 locus, 14 SNPs indicated significant risk effects, and notably, DYRK1A gene located in the Down Syndrome Critical Region indicated that a SNP located at upstream was likely functional. The expressional level of the DYRK1A mRNA in the brain was decreased in subjects with homozygous for the risk allele of the DYRK1A gene. However, the expression of DYRK1A mRNA was increased in all patients with LOAD, suggesting that DYRK1A protein could be neuroprotective. The assumption was supported by the evidence that in cell culture experiments, the expression of DYRK1A protein is increased by oxidative stress. These results indicated that construction of the linkage disequilibrium map by SNP genotyping makes possible to identify the disease-susceptibility genes.
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