| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
To search for polymorphic alleles influencing individual genetic susceptibility for osteoporosis, we have been analyzing genetic association of polymorphisms from a large pool of candidates with adjusted areal bone mineral density (aBMD). By now, we detected several candidate alleles significantly associated with aBMD level in single cohort (n=384, adult women). However, none of those variants have been ascertained to substantially contribute to the susceptibility in general. Here, to examine the reproducibility of those observed associations, we analyzed 1315 missense single nucleotide polymorphisms (SNPs) selected as common variant (>5% in Japanese) in a second stage association study for vertebral aBMD Z-score (L2-4) using a group of 380 adult Japanese women recruited independently from former cohort. By genotyping subjects for all the 1315 missense SNPs, and comparing the correlation coefficient between the genotypes and aBMD Z-score with those obtained from previous study, the reproducibility of the association was evaluated. However among all the analyzed SNPs, no alleles showed significant correlation in both groups (p<0.01), except one variant (W16S) in gonadotropin releasing hormone (GnRH) gene (r=0.14 in previous study p=0.005, and r=0.14 in current study p=0.007). This variant resides in the leader sequence of GnRH, and alters hydrophobicity of the central core region of the signal peptide. Considering from the strong candidacy of this selected polymorphism possibly affecting the sex hormone status and thus for bone mineral status, we assume that our screening is working as we expected. In addition, when the significance level was reduced to p<0.05, another functionally strong candidate gene LRP5 was included (as reported at the 26th annual meeting), supporting our assumption.
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