Summary of Research Project Results under JSPS FY2004
"Research for the Future Program"

1. Research Institution   Nippon Medical School
2. Research Area Life Sciences
3. Research Field Genome Research
4. Term of Project FY 2000 - FY 2004
5. Project Number 00L01408
6. Title of Project Genetic Analysis of Osteoporosis by Systematic SNP Typing

7. Project Leader

Name Institution, Department Title of Position
Mitsuru Emi Institute of Gerontology, Nippon Medical School Professor

8. Core Members


9. Summary of Research Results

Osteoporosis, due to loss of bone mineral and subsequent fragility, is clinically marked by increased risk of bone fracture in specially in the elderly. To identify multiple single nucleotide polymorphisms (SNP) that confer susceptibility to pathogenesis of osteoporosis, we carried out systematic search of SNPs in a genome-wide manner. We collected blood DNA and various clinical information including bone mineral density (BMD) from a large cohort of Japanese population. Those DNA were subjected to SNP analyses consisting of 5000 SNPs distributed widely in the human genome. Multiple susceptiblity SNPs were identified, some of them were followed by functional analysis in vitro.
We have collected epidemiological data, blood DNA, clinical information including BMD, form 3500 Japanese population through collaboration with five distinct osteoporosis centers in the country. This cohort will serve as variable resource for the osteoporosis research in Japan.We identified 64 SNPs on the 52 gene through systematic SNP analysis, correlation analysis, sib-pair analysis and linkage disequiribum analyses, the number of which far exceeds the outcome 20 SNPs from long-years of effort world-wide done in a candidate approach manner. Identified genes are likely candidates of bone mineral metabolism regulation, such as, vitamin D-binding protein in calcium-vitamin D-Parathyroid hormone system, gonadotropin-releasing hormone and pituitary glutamate cyclase in sex hormone regulation system, and, IRAK1, I-TRAF, and LIFR involved in regulation of differentiation of osteoblast and osteoclast.
Our finding enabled combined evaluation of multiple susceptibility SNPs for osteoporosis, and, opened the way to develop DNA-based diagnosis panel in a flat base format. We submitted two intellectual rights of licensing these novel findings, for practical application of them to routine clinical examination.

10. Key Words

( 1 ) osteoporosis ( 2 ) single nucleotide polymorphism (SNP) ( 3 ) systematic SNP analysis
( 4 ) DNA-based diagnosis technology ( 5 ) disease risk predictive diagnosis ( 6 ) association study
( 7 ) genetic epidemiology ( 8 ) adjusted bone mineral density ( 9 ) linkage disequiilibum