| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
To verify the direct association of MAPT locus with PSP and CBD, and to define its associated region, we investigated in Japanese population, who has only the H1 haplotype.
PSP and CBD are neurodegenerative diseases that are characterized by accumulations of hyperphosphorylated tau. Genetic studies have suggested an association of MAPT locus with PSP and CBD. However, since the 2 cM region including MAPT is in linkage disequilibrium (LD), forming two extended haplotypes H1 and H2, it is difficult to demonstrate a direct association between MAPT and these diseases in Caucasian population, who has H1 and H2 haplotypes. Genomic DNAs were extracted from unrelated patients with PSP [n=32] or CBD [n=10], and healthy individuals older than 65 years [n=60]. Eight single nucleotide polymorphisms covering MAPT and its adjacent 5' region, including rs7209436 (T/C), rs962885 (T/C), rs242557 (A/G), rs242562 (A/G), exon 4A C482T, exon 6 C139T, intron 9 C-47A, and rs2240756 (A/C), were examined. The rs962885-T/T and rs242562-A/A genotypes were associated with PSP (P=0.043 Odds ratio=2.51 and P=0.007 Odds ratio=3.53, respectively). When both of patients with PSP and CBD were analysed as a single group (PSP+CBD), the rs242557-A/A, rs242562-A/A, and exon 4A C482T-C/C genotypes were over-represented in PSP+CBD (P=0.040 Odds ratio=2.46, P=0.003 Odds ratio=3.64, and 0.018 Odds ratio=0.37, respectively). There is a significant LD (D'>0.5) across rs242557,rs242562,and exon 4A C482T, in PSP and PSP+CBD, but not in control. Haplotype analyses using these 3 markers showed that the haplotype of A-A-T is significant (24.9% in PSP+CBD, and 10.3% in control, P=0.014). Taken together, these data suggest that the specific haplotype of MAPT locus underlie the pathogenesis of PSP and CBD in Japanese population.
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