Clarification of genetic architecture of type 2 diabetes using expression analysis

• Project/Area Number: 21591124
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: HARA Kazuo 東京大学, 医学部附属病院, 特任准教授 (50359600)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 脂肪細胞 / インスリン抵抗性 / 遺伝子多型 / メタボリックシンドローム / 遺伝子発現

Research Abstract

We aim to clarify genetic architecture by expression analyses using human tissues which are involved in pathogenesis of type 2 diabetes and metabolic syndrome. Paired tissue samples of visceral and subcutaneous adipose tissues were obtained from patients undergone gastric surgery. Expression analysis revealed leptin gene expression level was positively correlated with BMI and adiponectin gene expression level was negatively associated with BMI after adjustment for body mass index(BMI). Principal component analysis showed gene expression profile of visceral fat was clearly distinguished from that of subcutaneous fat, which allowed us to predict origin of sample from gene expression data set. We observed expression levels of multiple genes in visceral fat tissue were substantially increased by 5 fold and significantly increased(P<10^<-6>) compared to those in subcutaneous fat, which were enriched in genes involved in inflammatory responses. These results suggest that accumulation of visceral fat play an important role in development of metabolic syndrome and type 2 diabetes in terms of alteration in transcriptome level.

Research Products

• [Journal Article] Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes (2012)
  • Author(s): Kodama K, Horikoshi M, Toda K, Yamada S, Hara K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H, Maeda S, Kadowaki T, Butte AJ
  • Journal Title: Proc Natl Acad Sci USA Volume: 109(18) Pages: 7049-54
• [Journal Article] Diabetes Genetics Replication and Meta-analysis(DIAGRAM) Consortium, Nakamura Y, Kadowaki T. A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations (2012)
  • Author(s): Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda K, Morizono T, Takahashi A, Horikoshi M, Nakamura M, Fujita H, Tsunoda T, Kubo M, Watada H, Maegawa H, Okada-Iwabu M, Iwabu M, Shojima N, Ohshige T, Omori S, Iwata M, Hirose H, KakuK, Ito C, Tanaka Y, Tobe K, Kashiwagi A, Kawamori R, Kasuga M, Kamatani N
  • Journal Title: Hum Mol Genet Pages: 22456796-22456796
• [Journal Article] Expression-based genome-wide association study links CD44 in adipose tissue with type 2 diabetes (2012)
  • Author(s): Kodama K,…Hara K, et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: (採択)(未定)
  • Peer Reviewed
• [Journal Article] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians (2011)
  • Author(s): Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC, Kwak SH, Ma RC, Yamamoto K, Adair LS, Aung T, Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, KimHL, Kim S, Kim YJ, Lee JJ, Lee NR, Li Y, Liu JJ, Lu W, Nakamura J, Nakashima E, NgDP, Tay WT, Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman AK, Morris AP, McCarthy MI ; DIAGRAM Consortium ; MuTHER Consortium, Takayanagi R, Park KS, Jia W, Chuang LM, Chan JC, Maeda S, Kadowaki T, Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han BG, Seielstad M
  • Journal Title: Nat Genet Volume: 44(1) Pages: 67-72
• [Journal Article] Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene (2011)
  • Author(s): Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K, Nishimura H, Kato M, Takeda N, Kohro T, Morita H, Taketani T, Morota T, Yamazaki T, Goto J, Tsuji S, Takamoto S, Nagai R, Hirata Y
  • Journal Title: Am J Cardiol Volume: 108(12) Pages: 1801-7
• [Journal Article] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians (2011)
  • Author(s): Cho YS, Yamauchi T, Hara K, Kadowaki T
  • Journal Title: Nature Genatics Volume: 44 Issue: 1 Pages: 67
  • DOI: 10.1038/ng.1019
  • Peer Reviewed
• [Journal Article] Evaluating Japanese patients with the Marfan syndrome using high-through put microarray-based mutational analysis of fibrillin-1 gene (2011)
  • Author(s): Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K, et al.
  • Journal Title: Am J Cardiol Volume: 108 Issue: 12 Pages: 1801-7
  • DOI: 10.1016/j.amjcard.2011.07.053
  • Peer Reviewed
• [Journal Article] Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance (2011)
  • Author(s): Kobayashi N, Ueki K, Okazaki Y, Iwane A, Kubota N, Ohsugi M, Awazawa M, Kobayashi M, Sasako T, Kaneko K, Suzuki M, Nishikawa Y, Hara K, Yoshimura K, Koshima I, Goyama s, Murakami K, Sasaki J, Nagai R, Kurokawa M, Sasaki T, Kadowaki T
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 108 Issue: 14 Pages: 5753-5758
  • DOI: 10.1073/pnas.1016430108
  • Peer Reviewed
• [Journal Article] A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. (2010)
  • Author(s): Yamauchi T, Hara K, Maeda S, et al
  • Journal Title: Nat. Genet. Volume: 42 Pages: 864-868
  • Peer Reviewed
• [Journal Article] Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension. (2010)
  • Author(s): Oishi Y, et al.
  • Journal Title: FASEB J. Volume: 24 Pages: 1780-1788
  • Peer Reviewed
• [Journal Article] Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hyoertension. (2010)
  • Author(s): Oishi Y, Manabe I, Imai Y, et al.
  • Journal Title: FASEB J Jan 26(Online)
  • Peer Reviewed
• [Journal Article] Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on 11 genes with strong evidence of the association. (2009)
  • Author(s): Miyake K, Yang W, Hara K, et al.
  • Journal Title: J Hum Genet 54 Pages: 236-41
  • NAID: 10030730081
  • Peer Reviewed
• [Journal Article] CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. (2009)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, et al.
  • Journal Title: Nat Med. 15 Pages: 914-20
  • Peer Reviewed
• [Presentation] Genetics of Type 2 diabetes in East Asia (2011)
  • Author(s): Hara K.
  • Organizer: 16th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Tokyo
  • Year and Date: 2011-10-22
• [Presentation] Comprehensive evaluation of type 2 diabetes susceptibility in the Japanese population by genome-wide imputation analysis using the 1000 Genomes Project data (2011)
  • Author(s): Hara K, Fujita H, Johnson TA, Horikoshi M, Maeda S, Tsunoda T, Kubo M, Nakamura Y, Kadowaki T.
  • Organizer: 12th ICHG/61thASHG
  • Place of Presentation: montreal, Canada
  • Year and Date: 2011-10-12
• [Presentation] 全ゲノム遺伝子発現解析をもとにした新規2型糖尿病遺伝子の同定 (2010)
  • Author(s): 原一雄
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2010-05-27