Genome study on osteoporosis and on imprinted genes

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 12204010
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagasaki Universty
• Principal Investigator: NIKAWA Norio Nagasaki University, Graduate School of Biomedical Sciences Department of Human Genetics, Professor, 大学院医歯薬学総合研究科, 教授 (00111170)
• Co-Investigator(Kenkyū-buntansha): KISHINO Tatsuya Nagasaki University, Center for Frontier Life Sciences, Division of Functional Genomics, Nagasaki University, Associate Professor, 先導生命科学研究支援センター, 助教授 (70315232)
• Project Period (FY): 2000 – 2004
• Keywords: osteoporosis / bone-mineral-density determinant / LRP5 gene / haplotype analysis / association study / single nucleotide polymorphism (SNP) / genomic imprinting / 7q32 region

Research Abstract

We reported results of an association study between BMD and 9 candidate genes (TGFB1, TGFBR2, SMAD2, SMAD3, SMAD4, INFB1, IFNAR1, FOS and LRP5), as well as of a case-control study of osteoporosis. Samples for the former association study included 481 general Japanese women. Among the 9 candidate genes, only LRP5 showed a significant association with BMD. We identified a strong linkage disequilibrium (LD) block within LRP5. Of four LPR5-SNPs that are located in the LD block, three gave relatively significant results: Women with C/C genotype at LRP5-9 SNP site had higher Adjusted BMD (AdjBMD) value, compared to those with C/T and T/T (p = 0.022); and likewise, G/G at LRP5-20 and C/C women at LRP5-21 showed higher AdjBMD than those with G/A or A/A (p = 0.039) and with C/T or T/T (p =0.053), respectively. The case- control study in another series of samples, consisting of 126 osteoporotic patients and 131 normal controls also gave a significant difference in allele frequency at LRP5-9 (p = 0.009). These results suggest that LRP5 is a BMD determinant and also contributes to a risk of osteoporosis.
By a comprehensive search for genes in human imprinting regions, 7q32, 15q11-q13 and 11p15.5, we identified such genes. Of the 12 genes identified at 7q32 region, 7 were shown to be involved in or escape imprinting. Some genes identified at the 15q region showed brain-specific imprinting or its erasure.

Research Products

• [Journal Article] Lack of association between the TGF-β1 gene polymorphisms and recurrent spontaneous abortion (2006)
  • Author(s): Amani D, Dehaghani SA, Zolghadri J, Ravangard F, Niikawa N, Yoshiura K, Ghaderi A
  • Journal Title: J Reprod Immunol (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of the Snurf-Snrpn IC transcript in the oocyte and putative role in the imprinting establishment of the mouse 7C imprinting domain (2006)
  • Author(s): Mapendano CK, Kishino T, Miyazaki K, Kondo S, Yoshiura K, Hishikawa Y, Koji T, Niikawa N
  • Journal Title: J Hum Genet (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome (2005)
  • Author(s): Saitoh S, Wada T, Okajima M, Takano K, Sudo A, Niikawa N
  • Journal Title: Brain Develop 27 Pages: 389-391
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association of polymorphic alleles of CTLA4 with inflammatory bowel disease in the Japanese (2005)
  • Author(s): Machida H, Tsukamoto K, Niikawa N, et al.
  • Journal Title: World J Gastroenterol 11 Pages: 4188-4193
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air (2005)
  • Author(s): Yamasaki Y, Kayashima T, Niikawa N, Kishino T, et al.
  • Journal Title: Hum Mol Genet 14 Pages: 2511-2530
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome. (2005)
  • Author(s): Saitoh S, Wada T, Okajima M, Takano K, Sudo A, Niikawa N
  • Journal Title: Brain Develop 27 Pages: 389-391
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of polymorphic alleles of CTLA4 with inflammatory bowel disease in the Japanese. (2005)
  • Author(s): Machida H, Tsukamoto K, Wen C-Y, Narumi Y, Shikuwa S, Isomoto H, Takeshima F, Mizuta Y, Niikawa N, Murata I, Kohno S.
  • Journal Title: World J Gastroenterol 11 (27) Pages: 4188-4193
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. (2005)
  • Author(s): Yamasaki Y, Kayashima T, Soejima H, Kinoshita A, Yoshiura KI, Matsumoto N, Ohta T, Urano T, Masuzaki H, Ishimaru T, Mukai T, Niikawa N, Kishino T.
  • Journal Title: Hum Mol Genet 14 Pages: 2511-2530
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TGFB1 mutations in four new families with Camurati-Engelmann disease : Confirmation of independently arising LAP-domain-specific mutations. (2004)
  • Author(s): Kinoshita A, Niikawa N, et al.
  • Journal Title: Am J Med Genet 127A Pages: 104-107
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] LRP5, low density lipoprotein receptor-related protein 5, is a determinant for bone mineral density (BMD) (2004)
  • Author(s): Mizuguchi T, Kishino T, Matsumoto N, Minakami H, Niikawa N, et al.
  • Journal Title: J Hum Genet 49 Pages: 80-86
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST-flanking region at human chromosome 7q32 (2004)
  • Author(s): Yamada T, Niikawa N, Kishino T, et al.
  • Journal Title: Genomics 83 Pages: 402-412
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TGFB1 mutations in four new families with Camurati-Engelmann disease : Confirmation of independently arising LAP-domain-specific mutations. (2004)
  • Author(s): Kinoshita A, Shirahama A, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Seidel J, Fukumaki Y, Ikegawa S, Niikawa N, Yoshiura K
  • Journal Title: AmJ Med Genet 127A Pages: 104-107
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] LRP5, low density lipoprotein receptor-related protein 5, is a determinant for bone mineral density (BMD). (2004)
  • Author(s): Mizuguchi T, Furuta I, Watanabe Y, Tsukamoto K, Tomita H, Tsujihata M, Ohta T, Kishino T, Matsumoto N, Minakami H, Niikawa N, Yoshiura K
  • Journal Title: J Hum Genet 49 Pages: 80-86
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST-flanking region at human chromosome 7q32. (2004)
  • Author(s): Yamada T, Mitsuya K, Kayashima T, Yamasaki K, Ohta T, Yoshiura K, Matsumoto N, Yamada H, Minakami H, Oshimura M, Niikawa N, Washino T
  • Journal Title: Genomics 83 (3) Pages: 402-412
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Atp10a, the mouse ortholog of the human imprinted ATP10C gene, escapes genomic imprinting (2003)
  • Author(s): Kayashima T, Yamasaki K, Niikawa N, Kishino T, et al.
  • Journal Title: Genomics 81 Pages: 644-647
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The novel imprinted carboxypeptidase A4 gene (CPA4) in the 7q32 imprinting domain (2003)
  • Author(s): Kayashima T, Yamasaki K, Niikawa N, Kishino T, et al.
  • Journal Title: Hum Genet 112 Pages: 220-226
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] On the conflicting reports of imprinting status of mouse ATP10a in the adult brain : Strain-background-dependent imprinting? (2003)
  • Author(s): Kayashima T, Ohta T, Niikawa N, Kishino T
  • Journal Title: J Hum Genet 48 Pages: 492-493
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a (2003)
  • Author(s): Yamasaki K, Niikawa N, Ogawa M, Wagstaff J, Kishino T, et al.
  • Journal Title: Hum Mol Genet 12 Pages: 837-847
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome (2003)
  • Author(s): Higashimoto K, Urano T, Niikawa N, Mukai T, Soejima H, et al.
  • Journal Title: Am J Hum Genet 73 Pages: 948-956
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Atp1Oa, the mouse ortholog of the human imprinted ATP10C gene, escapes genomic imprinting. (2003)
  • Author(s): Kayashima T, Yamasaki K, Joh K, Yamada T, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Mukai T, Niikawa N, Kishino T
  • Journal Title: Genomics 81 Pages: 644-647
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The novel imprinted carboxypeptidase A4 gene (CPA4) in the 7q32 imprinting domain. (2003)
  • Author(s): Kayashima T, Yamasaki K, Yamada T, Sakai H, Miwa N, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Kanetake H, Niikawa N, Kishino T
  • Journal Title: Hum Genet 112 Pages: 220-226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] On the conflicting reports of imprinting status of mouse ATP10a in the adult brain Strain-background-dependent imprinting? (2003)
  • Author(s): Kayashima T, Ohta T, Niikawa N, kishino T
  • Journal Title: J Hum Genet 48(9) Pages: 492-493
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. (2003)
  • Author(s): Yamasaki K, Joh K, Ohta T, Masuzaki H, Ishimaru T, Mukai T, Niikawa N, Ogawa M, Wagstaff J, Kishino T
  • Journal Title: Hum Mol Genet 12 Pages: 837-847
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome. (2003)
  • Author(s): Higashimoto K, Urano T, Sugiura K, Yatsuki H, Joh K, Wei Z, Iwakawa M, Ohashi H, Oshimura M, Niikawa N, Mukai T, Scejima. H
  • Journal Title: AmJ Hum Genet 73 (4) Pages: 948-956
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A catalog of 106 single nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-β1 (TGF-β1) and its signaling pathway (2002)
  • Author(s): Watanabe Y, Niikawa N, Yoshiura K, et al.
  • Journal Title: J Hum Genet 47 Pages: 478-483
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The novel gene,TSGA14, adjacent to the imprinted gene MEST escapes genomic imprinting (2002)
  • Author(s): Yamada T, Kayashima T, Nilkawa N, Kishino T, et al.
  • Journal Title: Gene 288 Pages: 57-63
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The human ASCL2 gene escaping genomic imprinting and its expression pattern (2002)
  • Author(s): Miyamoto T, Ishikawa M, Niikawa N, et al.
  • Journal Title: J Assist Reprod Genet 19 Pages: 240-244
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A catalog of 106 single nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-β1 (TGF-β1) and its signaling pathway. (2002)
  • Author(s): Watanabe Y, Kinoshita A, Yamada T, Ohta T, Kishino T, Matsumoto N, Ishikawa M, Niikawa N, Yoshiura K
  • Journal Title: J Hum Genet 47 Pages: 478-483
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The novel gene, TSGA14, adjacent to the imprinted gene MEST escapes genomic imprinting. (2002)
  • Author(s): Yamada T, Kayashima T, Yamasaki K, Ohta T, Yoshiura K, Matsumoto N, Fujimoto S, Niikawa N, Kishino T
  • Journal Title: Gene 288 (1-2) Pages: 57-63
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The human ASCL2 gene escaping genomic imprinting and its expression pattern. (2002)
  • Author(s): Miyamoto T, Hasuike S, Jinno Y, Soejima H, Yun K, Miura K, Ishikawa M, Niikawa N
  • Journal Title: J Assist Reprod Genet 19 Pages: 240-244
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lack of association between the TGF-β1 gene polymorphisms and recurrent spontaneous abortion.
  • Author(s): Amani D, Dehaghani SA, Zolghadri J, Ravangard F, Niikawa N, Yoshiura K, Ghaderi A
  • Journal Title: J Reprod Immunol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the Snurf-Snrpn IC transcript in the oocyte and putative role in the imprinting establishment of the mouse 7C imprinting domain.
  • Author(s): Mapendano CK, Kishino T, Miyazaki K, Kondo S, Yoshiura K, Hishikawa Y, Koji T, Niikawa N, Ohta T
  • Journal Title: J Hum Genet (in press)
  • Description: 「研究成果報告書概要(欧文)」より