JP2006296346A - Gene varying expression in relation to morbid state of diabetes and utilization thereof - Google Patents

Gene varying expression in relation to morbid state of diabetes and utilization thereof Download PDF

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JP2006296346A
JP2006296346A JP2005125689A JP2005125689A JP2006296346A JP 2006296346 A JP2006296346 A JP 2006296346A JP 2005125689 A JP2005125689 A JP 2005125689A JP 2005125689 A JP2005125689 A JP 2005125689A JP 2006296346 A JP2006296346 A JP 2006296346A
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Shuichi Kaneko
周一 金子
Toshinari Takamura
俊成 篁
Hirofumi Misu
博文 御簾
Taro Yamashita
太郎 山下
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Kanazawa University NUC
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a reagent utilizing a gene varying the expression in relation to a morbid state of diabetes and measuring the expression of the gene varying the expression in relation to the diabetes or obesity and to provide a method for detecting the diabetes or obesity using the reagent. <P>SOLUTION: The gene accelerates or attenuates the expression in a liver tissue of a patient suffering from human type 2 diabetes or obesity as compared with the liver tissue of a healthy human. The reagent comprises a nucleotide composed of a base sequence of at least one gene selected from the group consisting of a gene encoding a secretory protein or a nucleotide containing a part of the sequence thereof and is used for measuring the expression of a gene related to the type 2 diabetes and/or a gene related to the obesity. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子となり得る遺伝子の利用に関し、さらに本発明は糖尿病の病態と関連して発現が変動する遺伝子に関し、さらに該遺伝子の糖尿病や肥満症の診断もしくはリスク評価等への利用に関する。   The present invention relates to the use of genes that can be key molecules for the pathogenesis of sugar / lipid metabolism, diabetic complications, arteriosclerosis, etc., and the present invention relates to genes whose expression varies in relation to the pathology of diabetes, The present invention relates to the use of the gene for diagnosis or risk assessment of diabetes or obesity.

世界規模で増加し続ける２型糖尿病・肥満は網膜・腎・神経の合併症や虚血性心疾患などの動脈硬化症を促進し、人類のQOLと生命を脅かしている。肝臓は糖・脂質代謝に中心的な役割を担う重要な臓器である。２型糖尿病と肥満では、インスリンによる肝臓からの糖放出抑制作用は減弱しており、この現象はインスリン抵抗性と呼ばれる（非特許文献１および２を参照）。インスリン抵抗性は肝臓からの糖放出亢進による高血糖と、脂質の産生亢進による高脂血症をもたらし、ともに動脈硬化症を促進する。さらに肝臓は動脈硬化のリスクにつながる血管新生因子をはじめとする各種生理活性物質の生体内最大の産生臓器である。   Globally increasing type 2 diabetes and obesity promotes arteriosclerosis such as retinal, renal and neurological complications and ischemic heart disease, and threatens human QOL and life. The liver is an important organ that plays a central role in glucose and lipid metabolism. In type 2 diabetes and obesity, the action of insulin to suppress sugar release from the liver is attenuated, and this phenomenon is called insulin resistance (see Non-Patent Documents 1 and 2). Insulin resistance leads to hyperglycemia due to increased glucose release from the liver and hyperlipidemia due to increased lipid production, both of which promote arteriosclerosis. Furthermore, the liver is the largest organ that produces various physiologically active substances, including angiogenic factors that lead to the risk of arteriosclerosis.

Michael MD. et al., Mol. Cell 6:87-97, 2000Michael MD. Et al., Mol. Cell 6: 87-97, 2000 Saltiel AR. et al., Nature 414:799-806, 2001Saltiel AR. Et al., Nature 414: 799-806, 2001

本発明は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子となり得る遺伝子、ならびに該遺伝子の糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作る原因の解明への使用方法を提供する。   The present invention relates to a gene that can be a key molecule for the pathogenesis of sugar / lipid metabolism, diabetic complications, arteriosclerosis, and the like, and the pathogenesis of the gene for sugar / lipid metabolism, diabetic complications, arteriosclerosis, etc. Provide usage to elucidate the cause.

本発明は、糖尿病の病態と関連して発現が変動する遺伝子を利用した、糖尿病や肥満症に関連して発現が変動する遺伝子の発現を測定する試薬および該試薬を用いた糖尿病、肥満症、糖尿病性合併症、動脈硬化症などの検出方法の提供を目的とする。   The present invention relates to a reagent for measuring the expression of a gene whose expression varies in relation to diabetes or obesity, using a gene whose expression varies in relation to the pathological condition of diabetes, and diabetes, obesity, The purpose is to provide a method for detecting diabetic complications, arteriosclerosis, and the like.

本発明者はこれまで、正常肝と各種肝疾患のSAGE、およびこれまでのDNAチップ解析から得た60万発現遺伝子を超える世界最大の肝臓発現遺伝子データベースを構築し、肝臓病の解析をすすめてきた。その過程で独自に開発したcDNA マイクロアレイを用いて、２型糖尿病患者の肝臓に発現する遺伝子のプロファイルを解析したところ、従来の研究手法では異常がないと考えられていた２型糖尿病患者の肝臓において、糖代謝に直接に関連する遺伝子だけでなく、血管新生因子などの血管合併症に関連した多彩な既知遺伝子の発現が亢進していることを見出した（Takamura T. et al., Diabetologia 47:638-647, 2004）。これら既知の遺伝子は、２型糖尿病の病態を形作っている可能性がある。これらの知見は、肝由来分泌蛋白のなかに、２型糖尿病や肥満症状態の肝臓が、血管合併症をはじめとする糖尿病の病態を形作る未知の分泌蛋白が存在する可能性を示唆していた。そこで今回、この独創的な研究をさらに発展させ、Serial analysis of gene expression法（以下SAGE法）を用いて、２型糖尿病患者の肝臓が産生する遺伝子を、機能不明な未知遺伝子を含めて同定し、それらの中でインスリン抵抗性と関連して発現亢進・減弱する分泌タンパクをコードする遺伝子群を同定し、本発明を完成させるに至った。   The present inventor has so far established the world's largest liver expression gene database that exceeds 600,000 expression genes obtained from SAGE of normal liver and various liver diseases and DNA chip analysis so far, and has been promoting analysis of liver diseases. It was. In the process, we analyzed the profile of genes expressed in the liver of type 2 diabetic patients using a cDNA microarray developed independently. In the liver of type 2 diabetics, which was thought to be normal by conventional research methods, , We found that expression of various known genes related to vascular complications such as angiogenic factors as well as genes directly related to glucose metabolism was increased (Takamura T. et al., Diabetologia 47: 638-647, 2004). These known genes may shape the pathology of type 2 diabetes. These findings suggested that liver-derived secretory proteins may have unknown secreted proteins that form the pathology of diabetes, including vascular complications, in type 2 diabetic and obese livers. . Therefore, this original research is further developed, and the gene produced by the liver of type 2 diabetic patients, including unknown genes with unknown functions, is identified using the Serial analysis of gene expression method (hereinafter referred to as SAGE method). Among them, a group of genes encoding secreted proteins whose expression is increased or decreased in association with insulin resistance has been identified, and the present invention has been completed.

すなわち、本発明の態様は以下の通りである。
[１] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者または肥満症患者の肝臓組織で発現が亢進または減弱している遺伝子であって、分泌タンパク質をコードしている以下の遺伝子からなる群から選択される少なくとも１つの遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを含む２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 That is, the aspects of the present invention are as follows.
[1] A gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic or obese patient as compared with the liver tissue of a normal human, and which encodes a secreted protein A reagent for measuring the expression of a type 2 diabetes-related gene and / or an obesity-related gene comprising a nucleotide comprising a nucleotide sequence of at least one gene selected from the group consisting of:

(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 (1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80

[２] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がヒト血中HbA1c値と相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[１]の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [2] A gene whose expression is increased or decreased in the liver tissue of a human type 2 diabetes patient is at least selected from the group consisting of the following genes whose increased or decreased expression correlates with human blood HbA1c level: A reagent for measuring the expression of a type 2 diabetes-related gene and / or obesity-related gene of [1], which is one gene.

(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 (1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1

[３] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がHOMA-Rと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[１]の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [3] At least one gene whose expression is enhanced or attenuated in liver tissue of a human type 2 diabetic patient is selected from the group consisting of the following genes whose expression is correlated with HOMA-R: A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene of [1], which is a gene.

(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) (42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)

[４] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がMCRと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[１]の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [4] The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with MCR: A reagent for measuring the expression of a type 2 diabetes-related gene and / or obesity-related gene according to [1].

(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 (42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10

[５] ヒト肥満症患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がBMIと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[１]の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [5] The gene whose expression is enhanced or attenuated in the liver tissue of a human obese patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with BMI: [1] A reagent for measuring the expression of type 2 diabetes-related gene and / or obesity-related gene.

(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 (15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58

[６] 少なくとも５つの遺伝子を含む[１]〜[５]のいずれかの２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [6] A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to any one of [1] to [5], which comprises at least 5 genes.

[７] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを固相化したマイクロアレイを含む[１]〜[６]のいずれかの２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [7] A solid phase comprising a nucleotide comprising a nucleotide sequence of a gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient or a partial sequence thereof compared with that of a normal human liver tissue A reagent for measuring the expression of type 2 diabetes-related gene and / or obesity-related gene of any one of [1] to [6].

[８] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドをターゲットとしたプローブまたはプライマーを含む[１]〜[６]のいずれかの２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。 [8] The target is a nucleotide comprising a nucleotide sequence of a gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient compared to the liver tissue of a normal human subject, or a nucleotide containing a partial sequence thereof. A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to any one of [1] to [6], comprising a probe or primer.

[９] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子であって、分泌タンパク質をコードしている以下の遺伝子からなる群から選択される少なくとも１つの遺伝子について、被検体における発現を測定し、該遺伝子の発現が正常人に比較して亢進または減弱している場合に前記被検体が２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症に罹患しているか、または罹患するリスクがあると判断する方法。 [9] A gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient as compared with the liver tissue of a normal human subject, and comprising the following genes encoding secreted proteins: For at least one selected gene, the expression in the subject is measured, and when the expression of the gene is increased or decreased compared to a normal person, the subject is type 2 diabetes, obesity, diabetic complication To determine that you are suffering from, or at risk of suffering from, or arteriosclerosis.

(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 (1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80

[１０] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がヒト血中HbA1c値と相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[９]の方法。 [10] The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least selected from the group consisting of the following genes whose increased or decreased expression correlates with human blood HbA1c value: The method according to [9], which is one gene.

(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 (1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1

[１１] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がHOMA-Rと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[９]の方法。 [11] The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one selected from the group consisting of the following genes whose expression is correlated with HOMA-R The method according to [9], which is a gene.

(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) (42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)

[１２] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がMCRと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[９]の方法。 [12] The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with MCR: A certain [9] method.

(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 (42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10

[１３] ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がBMIと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である[９]の方法。 [13] The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with BMI: A certain [9] method.

(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 (15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58

[１４] 少なくとも５つの遺伝子について被検体における発現を測定する[９]〜[１３]のいずれかの方法。 [14] The method according to any one of [9] to [13], wherein the expression in the subject is measured for at least 5 genes.

[１５] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを固相化したマイクロアレイを用いる[９]〜[１４]のいずれかの方法。 [15] A solid phase comprising a nucleotide comprising a nucleotide sequence of a gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetic patient or a partial sequence thereof as compared with the liver tissue of a normal human subject The method according to any one of [9] to [14], wherein the microarray is used.

[１６] ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドをターゲットとしたリアルタイムPCRにより該遺伝子の発現を解析することを含む[９]〜[１４]のいずれかの方法。 [16] The target is a nucleotide comprising a nucleotide sequence of a gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient compared with that of a normal human liver, or a nucleotide containing a partial sequence thereof. The method according to any one of [9] to [14], which comprises analyzing expression of the gene by real-time PCR.

[１７] [１]〜[８]のいずれかの２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬を含む２型糖尿病、肥満症、糖尿病性合併症および動脈硬化症の検出またはリスク判定のためのキット。 [17] Type 2 diabetes, obesity, diabetic complications and arteriosclerosis comprising a reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to any one of [1] to [8] Kit for detection or risk assessment of illness.

実施例に示すように、２型糖尿病患者または肥満症患者の肝臓と正常人の肝臓との間で、病態ごとに発現が変動する遺伝子群を見出した。該遺伝子群は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子となり得、該遺伝子を利用することにより、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作る機構を解明することができる。該遺伝子群に属する遺伝子の発現を調べることにより、２型糖尿病、糖尿病性合併症、動脈硬化症または肥満症の病因を解明することができ、また２型糖尿病、糖尿病性合併症または動脈硬化症または肥満症の診断、２型糖尿病、糖尿病性合併症、動脈硬化症または肥満症に罹るリスクを評価することができる。さらに、２型糖尿病や肥満症の新規治療法の開発につながることが期待される   As shown in the Examples, a group of genes whose expression varies depending on the pathological condition between the livers of type 2 diabetic patients or obese patients and normal livers was found. This gene group can be a key molecule that makes pathological conditions such as sugar / lipid metabolism, diabetic complications, arteriosclerosis, etc. By using this gene, sugar / lipid metabolism, diabetic complications, arteriosclerosis, etc. It is possible to elucidate the mechanism of the pathophysiology. By examining the expression of genes belonging to the gene group, the etiology of type 2 diabetes, diabetic complications, arteriosclerosis or obesity can be elucidated, and type 2 diabetes, diabetic complications or arteriosclerosis Alternatively, the risk of developing obesity diagnosis, type 2 diabetes, diabetic complications, arteriosclerosis or obesity can be assessed. Furthermore, it is expected to lead to the development of new treatments for type 2 diabetes and obesity

本発明の糖尿病の病態または肥満と関連して発現変動する遺伝子は、２型糖尿病患者または肥満症患者の肝臓と正常人の肝臓との間で発現に差がある遺伝子であり、正常人の肝臓に比較して２型糖尿病患者または肥満症患者の肝臓における発現が亢進または減弱している遺伝子である。さらに、本発明の遺伝子は細胞外に分泌される分泌性タンパク質をコードする遺伝子である。ここで２型糖尿病とはインスリンの分泌量の低下やインスリンに対する感受性の低下により発症するタイプの糖尿病である。また、正常人とは２型糖尿病の病態を呈していない者をいい、具体的には肝臓または骨格筋におけるインスリン抵抗性が正常値である者、すなわち耐糖能が正常な者をいう。２型糖尿病の病態として、血液中HbA1c（ヘモグロビンA1c）濃度が高くなり、インスリン抵抗性（肝臓におけるインスリン抵抗性および骨格筋におけるインスリン抵抗性）が高まることが挙げられる。肝臓におけるインスリン抵抗性は、HOMA-R(homeostasis model assessment)の測定により決定することができ、HOMA-Rの数値が大きいほど肝臓におけるインスリン抵抗性が強いと判断される。また、骨格筋におけるインスリン抵抗性は、MCR(glucose metabolic clearance rate)の測定により決定することができ、MCRの数値が大きいほど骨格筋のインスリン抵抗性が強いと判断される。HOMA-R値は、空腹時血糖(mg/dl)×空腹時インスリン濃度(IRI)(μU/ml)/405で示され（Matthews DR et al., Diabetologia 28:412-419, 1985）、正常人ではこの値が１前後である。MCR値は、例えばDeFronzo RA et al., Am J Physiol 237:E214-223, 1979に記載の方法で測定することができる。肥満症患者は、BMI（Body Mass index）が高値を示す患者であり、BMIは体重(kg)／身長(m)2で示される。BMIが25以上の場合、肥満症であると判定される。 The gene whose expression changes in relation to the pathological condition of obesity or obesity of the present invention is a gene whose expression is different between the liver of a type 2 diabetic or obese patient and the liver of a normal person, and the liver of a normal person In comparison with the above, it is a gene whose expression in the liver of type 2 diabetic patients or obese patients is increased or decreased. Furthermore, the gene of the present invention is a gene encoding a secretory protein secreted extracellularly. Here, type 2 diabetes is a type of diabetes that develops due to a decrease in the secreted amount of insulin and a decrease in sensitivity to insulin. A normal person refers to a person who does not exhibit type 2 diabetes, specifically a person who has normal insulin resistance in the liver or skeletal muscle, that is, a person who has normal glucose tolerance. As a pathological condition of type 2 diabetes, the concentration of HbA1c (hemoglobin A1c) in blood is increased, and insulin resistance (insulin resistance in the liver and insulin resistance in skeletal muscle) is increased. Insulin resistance in the liver can be determined by measurement of HOMA-R (homeostasis model assessment), and the larger the value of HOMA-R, the stronger the insulin resistance in the liver. Insulin resistance in skeletal muscle can be determined by measurement of MCR (glucose metabolic clearance rate), and it is determined that insulin resistance of skeletal muscle is stronger as the value of MCR is larger. HOMA-R values are expressed as fasting blood glucose (mg / dl) x fasting insulin concentration (IRI) (μU / ml) / 405 (Matthews DR et al., Diabetologia 28: 412-419, 1985), normal In humans, this value is around 1. The MCR value can be measured by the method described in, for example, DeFronzo RA et al., Am J Physiol 237: E214-223, 1979. An obese patient is a patient whose BMI (Body Mass index) shows a high value, and BMI is represented by body weight (kg) / height (m) 2 . If the BMI is 25 or more, it is determined to be obese.

本発明の２型糖尿病の病態または肥満症と関連して発現変動する遺伝子は、血液中HbA1c値、HOMA-R、MCRおよびBMIのいずれか一つと有意の相関が認められる遺伝子である。ここで、有意の相関が認められるとは、例えば血液中HbA1c値、HOMA-R、MCRおよびBMIの各測定値と各遺伝子の発現レベルの関係を線形相関解析により解析した場合に有意に相関が認められることをいう。   The gene whose expression changes in association with the pathological condition of obesity or type 2 diabetes of the present invention is a gene that is significantly correlated with any one of blood HbA1c level, HOMA-R, MCR and BMI. Here, a significant correlation is observed when, for example, the relationship between the measured values of blood HbA1c, HOMA-R, MCR, and BMI and the expression level of each gene is analyzed by linear correlation analysis. It means being recognized.

血液中HbA1c値と有意の相関が認められる遺伝子として表３に示す１４遺伝子が、BMIと有意の相関が認められる遺伝子として表４に示す２９遺伝子が、HOMA-Rと有意の相関が認められる遺伝子として表５に示す６遺伝子が、MCRと有意の相関が認められる遺伝子として表６に示す２１遺伝子が挙げられる。本発明において、HbA1c値と有意の相関が認められる遺伝子をHbA1c病態関連遺伝子群、HOMA-Rと有意の相関が認められる遺伝子をHOMA-R病態関連遺伝子群、MCRと有意の相関が認められる遺伝子をMCR病態関連遺伝子群、BMIと有意の相関が認められる遺伝子をBMI病態関連遺伝子群と呼ぶことがある。このうち、HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群およびMCR病態関連遺伝子群を２型糖尿病関連遺伝子群ということができ、BMI病態関連遺伝子群を肥満症関連遺伝子群ということができる。なお、それぞれの遺伝子群には一部重複があるので、遺伝子の種類は全部で６２種類ある。これらの遺伝子には、機能が解明されていない遺伝子も含まれるが（表３から６の「Symbol」の欄において、c(n)orf(m)((n)および(m)は整数)、このような機能未知とされる遺伝子がコードするタンパク質についても、アミノ酸配列解析から、シグナルペプチドを有しており分泌タンパク質であることが判明している。なお、これらの遺伝子は、本発明において初めて、糖尿病や肥満と関連あることが見出された。   14 genes shown in Table 3 as genes that are significantly correlated with HbA1c levels in blood, and 29 genes shown in Table 4 as genes that are significantly correlated with BMI are genes that are significantly correlated with HOMA-R. 6 genes shown in Table 5 and 21 genes shown in Table 6 as genes that have a significant correlation with MCR. In the present invention, genes that are significantly correlated with the HbA1c value are genes that are significantly correlated with the HbA1c disease state-related gene group, genes that are significantly correlated with the HOMA-R are genes that are significantly correlated with the HOMA-R disease state-related gene group, and MCR. May be referred to as MCR disease state-related genes, and genes that are significantly correlated with BMI may be referred to as BMI disease state-related genes. Among these, the HbA1c disease state-related gene group, the HOMA-R disease state-related gene group, and the MCR disease state-related gene group can be referred to as a type 2 diabetes-related gene group, and the BMI disease state-related gene group can be referred to as an obesity-related gene group. Since each gene group has a partial overlap, there are 62 types of genes in total. These genes include genes whose functions have not been elucidated (in the “Symbol” column of Tables 3 to 6, c (n) orf (m) ((n) and (m) are integers), A protein encoded by such a gene whose function is unknown has also been found to be a secreted protein having a signal peptide by amino acid sequence analysis. It was found to be associated with diabetes and obesity.

表３に示す１４遺伝子の塩基配列を配列番号１（PVR）、配列番号２（LGALS8）、配列番号３（FCN3）、配列番号４（MMP24）、配列番号５（MDK）、配列番号６（NUCB2）、配列番号７（MMP11）、配列番号８（GPX3）、配列番号９（C14orf2）、配列番号１０（C14orf4）、配列番号１１（C10orf10）、配列番号１２（C6orf74）、配列番号１３（C9orf83）および配列番号１４（C8orf1）に表す。   The base sequences of the 14 genes shown in Table 3 are SEQ ID NO: 1 (PVR), SEQ ID NO: 2 (LGALS8), SEQ ID NO: 3 (FCN3), SEQ ID NO: 4 (MMP24), SEQ ID NO: 5 (MDK), SEQ ID NO: 6 (NUCB2). ), SEQ ID NO: 7 (MMP11), SEQ ID NO: 8 (GPX3), SEQ ID NO: 9 (C14orf2), SEQ ID NO: 10 (C14orf4), SEQ ID NO: 11 (C10orf10), SEQ ID NO: 12 (C6orf74), SEQ ID NO: 13 (C9orf83) And SEQ ID NO: 14 (C8orf1).

表４に示す２９遺伝子の塩基配列を配列番号１５（BMP2）、配列番号１６（LECT2）、配列番号１７（ADFP）、配列番号１８（BPAG1）、配列番号１９（SERPINF1）、配列番号２０（GNAS）、配列番号２１（AHSG）、配列番号２２（CCL16）、配列番号２３（AFM）、配列番号２４（LTBP1）、配列番号２５（C4BPA）、配列番号２６（LYZ）、配列番号４（MMP24）、配列番号２７（PSAP）、配列番号２８（HRG）、配列番号２９（FST）、配列番号３０（GPC3）、配列番号３１（GPLD1）、配列番号３２（GDF15）、配列番号３３（SPINT2）、配列番号３４（TNFRSF1A）、配列番号３５（c14orf123）、配列番号１４（c8orf1）、配列番号３６（c14orf32）、配列番号３７（c5orf13）、配列番号３８（c9orf10）、配列番号３９（c10orf107）、配列番号４０(c1orf38)および配列番号４１（c10orf58）に表す。   The base sequences of 29 genes shown in Table 4 are SEQ ID NO: 15 (BMP2), SEQ ID NO: 16 (LECT2), SEQ ID NO: 17 (ADFP), SEQ ID NO: 18 (BPAG1), SEQ ID NO: 19 (SERPINF1), SEQ ID NO: 20 (GNAS ), SEQ ID NO: 21 (AHSG), SEQ ID NO: 22 (CCL16), SEQ ID NO: 23 (AFM), SEQ ID NO: 24 (LTBP1), SEQ ID NO: 25 (C4BPA), SEQ ID NO: 26 (LYZ), SEQ ID NO: 4 (MMP24) SEQ ID NO: 27 (PSAP), SEQ ID NO: 28 (HRG), SEQ ID NO: 29 (FST), SEQ ID NO: 30 (GPC3), SEQ ID NO: 31 (GPLD1), SEQ ID NO: 32 (GDF15), SEQ ID NO: 33 (SPINT2), Sequence number 34 (TNFRSF1A), sequence number 35 (c14orf123), sequence number 14 (c8orf1), sequence number 36 (c14orf32), sequence number 37 (c5orf13), sequence number 38 (c9orf10), sequence number 39 (c10orf107), sequence It is represented by the number 40 (c1orf38) and the sequence number 41 (c10orf58).

表５に示す６遺伝子の塩基配列を配列番号４２（THBS1）、配列番号４３（CTSS）、配列番号４４（PON1）、配列番号４５（DEFB1）、配列番号４６（MAP2K2）および配列番号４７（PLA2G7）に示す。   The nucleotide sequences of the 6 genes shown in Table 5 are shown in SEQ ID NO: 42 (THBS1), SEQ ID NO: 43 (CTSS), SEQ ID NO: 44 (PON1), SEQ ID NO: 45 (DEFB1), SEQ ID NO: 46 (MAP2K2) and SEQ ID NO: 47 (PLA2G7). ).

さらに、表６に示す２１遺伝子の塩基配列を配列番号３６（THBS1）、配列番号４８（IGFBP1）、配列番号４９（SULF2）、配列番号５０（WNT5B）、配列番号５１（ADAMTS1）、配列番号５２（SEPP1）、配列番号５３（CHAD）、配列番号５４（DCN）、配列番号５５（CTSS）、配列番号５６（LBP）、配列番号４（MMP24）、配列番号５７（SPARCL1）、配列番号５８（LRG1）、配列番号５９（c14orf100）、配列番号３５（c14orf123）、配列番号９（C14orf2）、配列番号６０（C18orf10）、配列番号３７（C5orf13）、配列番号６１（C6orf79）、配列番号６２（C6orf80）および配列番号３８（C9orf10）に表す。括弧内の表示は、表中の「Symbol」を示す。   Furthermore, the base sequences of 21 genes shown in Table 6 are shown in SEQ ID NO: 36 (THBS1), SEQ ID NO: 48 (IGFBP1), SEQ ID NO: 49 (SULF2), SEQ ID NO: 50 (WNT5B), SEQ ID NO: 51 (ADAMTS1), and SEQ ID NO: 52. (SEPP1), SEQ ID NO: 53 (CHAD), SEQ ID NO: 54 (DCN), SEQ ID NO: 55 (CTSS), SEQ ID NO: 56 (LBP), SEQ ID NO: 4 (MMP24), SEQ ID NO: 57 (SPARCL1), SEQ ID NO: 58 ( LRG1), SEQ ID NO: 59 (c14orf100), SEQ ID NO: 35 (c14orf123), SEQ ID NO: 9 (C14orf2), SEQ ID NO: 60 (C18orf10), SEQ ID NO: 37 (C5orf13), SEQ ID NO: 61 (C6orf79), SEQ ID NO: 62 (C6orf80) ) And SEQ ID NO: 38 (C9orf10). The indication in parentheses indicates “Symbol” in the table.

本発明で用いるヌクレオチドは上記配列を含むヌクレオチドおよびその断片を含む。また、本発明に用いるヌクレオチドは、上記配列番号で示されるヌクレオチドとストリンジェントな条件下でハイブリダイズするヌクレオチドおよびその断片も含まれる。このようなヌクレオチドとしては、例えば、上記塩基配列との相同性の程度が、全体の平均で約80％以上、好ましくは約90％以上、より好ましくは約95％以上である塩基配列を含有するヌクレオチド等を挙げることが出来る。ハイブリダイゼーションは、カレント・プロトコールズ・イン・モレキュラー・バイオロジー（Current protocols in molecular biology（edited by Frederick M. Ausubel et al., 1987））に記載の方法等、当業界で公知の方法あるいはそれに準じる方法に従って行なうことができる。また、市販のライブラリーを使用する場合、添付の使用説明書に記載の方法に従って行なうことができる。ここで、「ストリンジェントな条件」とは、例えば、「１XSSC、0.1％ SDS、37℃」程度の条件であり、より厳しい条件としては「0.5XSSC、0.1％ SDS、42℃」程度の条件であり、さらに厳しい条件としては「0.2XSSC、0.1％ SDS、65℃」程度の条件である。このようにハイブリダイゼーションの条件が厳しくなるほどプローブ配列と高い相同性を有するヌクレオチドを単離を期待しうる。ただし、上記のSSC,SDSおよびに温度の条件の組み合わせは例示であり、当業者であればハイブリダイゼーションのストリンジェンシーを決定する上記もしくは他の要素（例えば、プローブ濃度、プローブの長さ、ハイブリダイゼーションの反応時間など）を適宜組み合わせることにより、上記と同様のストリンジェンシーを実現することが可能である。さらに、上記遺伝子のうちのいくつか（LGALS8、FCN3、MDK、GNAS、LTBP1、FST、GPLD1）には、バリアントが存在し、本発明のヌクレオチドは該バリアントの塩基配列を含むヌクレオチドまたはその断片も含む。   Nucleotides used in the present invention include nucleotides containing the above sequences and fragments thereof. The nucleotides used in the present invention also include nucleotides that hybridize with the nucleotides shown in the above SEQ ID NOs under stringent conditions and fragments thereof. Such nucleotides include, for example, a base sequence having a degree of homology with the above base sequence of about 80% or more, preferably about 90% or more, more preferably about 95% or more as a whole on average. A nucleotide etc. can be mentioned. Hybridization is a method known in the art such as the method described in Current protocols in molecular biology (edited by Frederick M. Ausubel et al., 1987) or the like. It can be done according to the method. Moreover, when using a commercially available library, it can carry out according to the method as described in an attached instruction manual. Here, “stringent conditions” are, for example, “1XSSC, 0.1% SDS, 37 ° C.” conditions, and more severe conditions are “0.5XSSC, 0.1% SDS, 42 ° C.” conditions. There are more severe conditions such as “0.2XSSC, 0.1% SDS, 65 ° C.”. As the hybridization conditions become more severe, it can be expected to isolate a nucleotide having high homology with the probe sequence. However, combinations of the above SSC, SDS, and temperature conditions are exemplary, and those skilled in the art will understand the above or other factors that determine the stringency of hybridization (eg, probe concentration, probe length, hybridization). It is possible to achieve the same stringency as described above by appropriately combining the reaction time and the like. Furthermore, some of the above genes (LGALS8, FCN3, MDK, GNAS, LTBP1, FST, GPLD1) have variants, and the nucleotides of the present invention also include nucleotides containing the nucleotide sequences of the variants or fragments thereof. .

本発明で用いるヌクレオチドとしては、上記遺伝子のセンス鎖よりなるヌクレオチド、アンチセンス鎖よりなるヌクレオチドのいずれをも用いることができる。   As the nucleotide used in the present invention, either a nucleotide comprising a sense strand of the above gene or a nucleotide comprising an antisense strand can be used.

表３〜６に示す遺伝子のうち、「DM（２型糖尿病患者群）/NGT（耐糖能正常患者群） by SAGE」で表される値が１を超えるものが２型糖尿病の病態または肥満症と関連して発現が亢進する遺伝子であり、１未満のものが２型糖尿病の病態または肥満症と関連して発現が減弱する遺伝子である。また、値がより大きいか、もしくは値がより小さい遺伝子ほど、２型糖尿病の病態または肥満症との関連がより強い遺伝子であるといえる。従って、表に挙げた遺伝子のうち、表中の「DM（２型糖尿病患者群）/NGT（耐糖能正常患者群） by SAGE」で表される値が２以上のものまたは0.5以下の遺伝子をより好適に用いることができる。   Among the genes shown in Tables 3-6, those with a value expressed as “DM (type 2 diabetic patient group) / NGT (normal glucose tolerance patient group) by SAGE” are more than 1 type 2 diabetic condition or obesity The genes whose expression is increased in association with the phenotype and those less than 1 are genes whose expression is attenuated in connection with the pathology of type 2 diabetes or obesity. Moreover, it can be said that a gene with a larger value or a smaller value is a gene having a stronger association with the pathology of type 2 diabetes or obesity. Therefore, among the genes listed in the table, genes with a value represented by “DM (type 2 diabetic patients) / NGT (normal glucose tolerance patients) by SAGE” in the table are 2 or more or 0.5 or less. It can be used more suitably.

これらの遺伝子群に属する各遺伝子は公知のSAGE：Serial Analysis of GeneExpression法（Yamashita T. et al., Biochem Biophys Res Commun 269:110-116, 2000; Yamashita T. et al., Biochem Biophys Res Commun 282:647-654, 2001; Science 276:1268, 1997; Cell 88:243, 1997; Science 270:484, 1995; Nature 389:300, 1997; 米国特許第5,695,937 号公報; 特表平10-511002号公報）によって特定されたものである。このSAGE法は、任意の細胞で発現している遺伝子から調製したcDNAのそれぞれについて、個々を特徴づける10塩基対のDNA配列（Tag）を決定する方法である。また、得られた全てのTagから個々のTagの割合を算出することによって、各遺伝子の発現頻度（コピー数）を決定することもできる。   Each gene belonging to these gene groups is a known SAGE: Serial Analysis of GeneExpression method (Yamashita T. et al., Biochem Biophys Res Commun 269: 110-116, 2000; Yamashita T. et al., Biochem Biophys Res Commun 282 : 647-654, 2001; Science 276: 1268, 1997; Cell 88: 243, 1997; Science 270: 484, 1995; Nature 389: 300, 1997; U.S. Pat.No. 5,695,937; JP 10-511002 ). This SAGE method is a method for determining a 10 base pair DNA sequence (Tag) characterizing each cDNA prepared from a gene expressed in an arbitrary cell. Moreover, the expression frequency (copy number) of each gene can also be determined by calculating the ratio of each tag from all the obtained tags.

また、表にはNCBI(National Center for Biotechnology Information)のUnigene（http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene）のアクセッション番号が示され、該番号でデータベースにアクセスすることで、それぞれの遺伝子の配列情報を容易に得ることが可能である。   The table also shows the accession numbers of Unigene (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene) of NCBI (National Center for Biotechnology Information). By accessing the database at, it is possible to easily obtain the sequence information of each gene.

これらの遺伝子は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子となり得る。   These genes can be key molecules for pathological conditions such as sugar / lipid metabolism, diabetic complications, and arteriosclerosis.

従って、これらの遺伝子は、糖・脂質代謝の研究、２型糖尿病や肥満症の病因解明、２型糖尿病の検出（診断）、２型糖尿病に罹患するリスクの評価、肥満症になるリスク評価、ならびに糖尿病や肥満症の新規な治療法の開発に利用することができる。また、これらの遺伝子は、インスリン抵抗性に密接に関連しており、インスリン抵抗性の判定にも利用することができる。さらに、これらの遺伝子は糖尿病性合併症とも関連しており、糖尿病性合併症の検出（診断）または糖尿病性合併症に罹患するリスクの判定に利用することができる。さらに、糖尿病、肥満およびインスリン抵抗性は動脈硬化症の危険因子であり、これらの遺伝子は動脈硬化症とも密接に関連しており、動脈硬化症の検出（診断）および動脈硬化症に罹患するリスクの判定に用いることもできる。なお、糖尿病性合併症としては、例えば、糖尿病性網膜症、糖尿病性腎症、糖尿病性神経障害、糖尿病性大血管症、心筋梗塞、脳卒中等が挙げられる。   Therefore, these genes are used to study sugar / lipid metabolism, elucidate the etiology of type 2 diabetes and obesity, detect (diagnose) type 2 diabetes, evaluate the risk of suffering from type 2 diabetes, assess the risk of becoming obese, It can also be used to develop new treatments for diabetes and obesity. Moreover, these genes are closely related to insulin resistance, and can be used for determination of insulin resistance. Furthermore, these genes are also associated with diabetic complications and can be used to detect (diagnose) diabetic complications or to determine the risk of suffering from diabetic complications. In addition, diabetes, obesity and insulin resistance are risk factors for arteriosclerosis, and these genes are also closely related to arteriosclerosis, detecting (diagnosing) arteriosclerosis and risk of suffering from arteriosclerosis It can also be used for determination. Examples of diabetic complications include diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic macroangiopathy, myocardial infarction, and stroke.

２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病因解明のためには、本発明の遺伝子の肝臓での発現状況を調べる必要がある。また、本発明の遺伝子の肝臓での発現状況を調べることにより、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患しているかどうかの検出（診断）を行うことができ、さらに、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患するリスクを有しているかどうかの評価をすることができる。なお、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患している場合でも、これらの疾患の初期において、HOMA-R、HbA1c等の病態を検出可能に呈さない場合がある。本願発明のヌクレオチドを用いることにより、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病態に関連した遺伝子の発現の変動を測定でき、病態を検出可能に呈さない場合であっても、２型糖尿病、糖尿病性合併症または動脈硬化症に罹患していると判断できる場合がある。また、このような状態は今後２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病態を検出可能に呈する可能性のある状態であり、この点２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病態を呈するリスクを評価することもできる。   In order to elucidate the etiology of type 2 diabetes, obesity, diabetic complications or arteriosclerosis, it is necessary to examine the expression status of the gene of the present invention in the liver. Further, by examining the expression state of the gene of the present invention in the liver, it is possible to detect (diagnose) whether the subject suffers from type 2 diabetes, obesity, diabetic complications or arteriosclerosis. In addition, it can be assessed whether the subject is at risk of suffering from type 2 diabetes, obesity, diabetic complications or arteriosclerosis. Even when suffering from type 2 diabetes, obesity, diabetic complications or arteriosclerosis, pathological conditions such as HOMA-R and HbA1c may not be detectable in the early stages of these diseases. By using the nucleotide of the present invention, it is possible to measure changes in gene expression related to the pathology of type 2 diabetes, obesity, diabetic complications or arteriosclerosis, and even when the pathology does not present detectable It may be determined that the patient is suffering from type 2 diabetes, diabetic complications or arteriosclerosis. In addition, such a condition is a condition in which it is possible to detect the pathological condition of type 2 diabetes, obesity, diabetic complications or arteriosclerosis in the future, and this is a type 2 diabetes, obesity, diabetic complication. It is also possible to assess the risk of presenting the disease state of atherosclerosis or arteriosclerosis.

このような検出または評価のためには、HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群、MCR病態関連遺伝子群およびBMI病態関連遺伝子群に属する遺伝子の中の少なくとも１種、好ましくは少なくとも２種、さらに好ましくは少なくとも５種、さらに好ましくは少なくとも10種、さらに好ましくは少なくとも20種、さらに好ましくは少なくとも30種、さらに好ましくは全部を用いて、遺伝子の発現の亢進または減弱を測定すればよい。また、HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群、MCR病態関連遺伝子群およびBMI病態関連遺伝子群のそれぞれの群に属する遺伝子の中から少なくとも１種、好ましくは少なくとも２種、さらに好ましくは５種、さらに好ましくは少なくとも10種、さらに好ましくは全部を用いてもよい。特にBMI病態関連遺伝子群は肥満症と関連していると予測されるので、肥満になるリスクの評価のために用いることができる。   For such detection or evaluation, at least one of the genes belonging to the HbA1c disease state-related gene group, the HOMA-R disease state-related gene group, the MCR disease state-related gene group and the BMI disease state-related gene group, preferably at least 2 Increase or decrease of gene expression may be measured using species, more preferably at least 5, more preferably at least 10, more preferably at least 20, more preferably at least 30, more preferably all. . In addition, at least one, preferably at least two, more preferably among the genes belonging to each of the HbA1c disease state-related gene group, HOMA-R disease state-related gene group, MCR disease state-related gene group, and BMI disease state-related gene group Five, more preferably at least 10, more preferably all may be used. In particular, BMI disease state-related genes are predicted to be associated with obesity and can be used to evaluate the risk of becoming obese.

これらの遺伝子の発現の亢進または減弱の測定のためには、上記の遺伝子の塩基配列の全部または一部を含むヌクレオチドをプローブまたはプライマーとして用いて遺伝子発現の程度を測定すればよい。遺伝子発現の程度は、ノーザンブロット法、RT-PCR法、リアルタイムPCR法、in situ ハイブリダイゼーション法、マイクロアレイ（マイクロチップ）を用いた方法等により測定することが可能であり、ここに挙げた方法はいずれも公知の方法で行うことができる。遺伝子の発現は、上記遺伝子の一部から転写されたメッセンジャーRNA（mRNA）の量を測定すればよく、該mRNAにハイブリダイズするヌクレオチドプローブまたはプライマーの使用により測定することができる。   In order to measure the increase or decrease in the expression of these genes, the degree of gene expression may be measured using nucleotides containing all or part of the base sequences of the above genes as probes or primers. The degree of gene expression can be measured by Northern blotting, RT-PCR, real-time PCR, in situ hybridization, a method using a microarray (microchip), etc. Any of them can be carried out by a known method. The expression of the gene can be measured by measuring the amount of messenger RNA (mRNA) transcribed from a part of the gene and using a nucleotide probe or primer that hybridizes to the mRNA.

プローブまたはプライマーの塩基長は、10〜50bp、好ましくは15〜25bpである。   The base length of the probe or primer is 10 to 50 bp, preferably 15 to 25 bp.

被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患しているかどうかの検出（診断）、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患するリスクを有しているかどうかの評価のためには試料サンプルとして、肝臓生検サンプル、血清、血漿等を用いればよい。   Detection (diagnosis) of whether the subject has type 2 diabetes, obesity, diabetic complications or arteriosclerosis, subject has type 2 diabetes, obesity, diabetic complications or arteriosclerosis In order to evaluate whether or not there is a risk, a liver biopsy sample, serum, plasma or the like may be used as a sample sample.

HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群、MCR病態関連遺伝子群およびBMI病態関連遺伝子群に属する遺伝子の１種以上の発現が正常人に比較して亢進または減弱している場合に、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患していると診断することができ、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患するリスクを有していると評価することができる。この際、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病態と関連して発現が亢進する遺伝子の場合は、その亢進の程度を定量することにより、また、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病態と関連して発現が減弱する遺伝子の場合は、その減弱の程度を定量することにより、より正確に、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患していると診断することができ、被験体が２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患するリスクを有していると評価することができる。例えば、遺伝子の発現がより亢進しているか、またはより減弱していれば、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の重篤度が高いと判断し得るし、また遺伝子の発現がより亢進しているか、またはより減弱していれば、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹るリスクが高いと評価することができる。   When the expression of one or more genes belonging to the HbA1c disease-related gene group, HOMA-R disease-related gene group, MCR disease-related gene group, and BMI disease-related gene group is increased or attenuated compared to normal individuals, The subject can be diagnosed with type 2 diabetes, obesity, diabetic complications or arteriosclerosis, and the subject has type 2 diabetes, obesity, diabetic complications or arteriosclerosis Can be evaluated as having the risk of In this case, in the case of a gene whose expression is increased in association with type 2 diabetes, obesity, diabetic complications or arteriosclerotic pathology, by quantifying the degree of the enhancement, type 2 diabetes, obesity A gene whose expression is attenuated in relation to the pathology of cerebral disease, diabetic complications or arteriosclerosis, the subject can be more accurately determined by quantifying the degree of attenuation so that the subject has type 2 diabetes, obesity, diabetes Can be diagnosed as having sexual complications or arteriosclerosis and assessing that the subject is at risk of suffering from type 2 diabetes, obesity, diabetic complications or arteriosclerosis Can do. For example, if the expression of the gene is more enhanced or attenuated, it can be determined that type 2 diabetes, obesity, diabetic complications or arteriosclerosis is more severe, and If expression is more upregulated or attenuated, it can be assessed that the risk of developing type 2 diabetes, obesity, diabetic complications or arteriosclerosis is high.

さらに、遺伝子の発現を直接測定するばかりでなく、遺伝子発現産物を測定してもよい。例えば、上記遺伝子がコードするタンパク質に対する抗体を用いることにより遺伝子発現産物を測定することができる。本発明は、２型糖尿病患者または肥満症患者の肝臓と正常人の肝臓との間で、病態ごとに発現が変動する遺伝子がコードするタンパク質、該タンパク質に対する抗体、これらを含む試薬等も包含する。   In addition to directly measuring gene expression, gene expression products may also be measured. For example, the gene expression product can be measured by using an antibody against the protein encoded by the gene. The present invention also includes a protein encoded by a gene whose expression varies depending on the pathological condition between the liver of a type 2 diabetic or obese patient and a normal human liver, an antibody against the protein, a reagent containing these, and the like. .

本発明は、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の病因解明のための、２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症の検出（診断）のための、および２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症に罹患するリスクを評価するための、ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを含む２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬を包含する。該試薬は、前記遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドをプローブまたはプライマーとして含む試薬であり、また前記遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを固相化したマイクロアレイ等の基板である。   The present invention is for detection (diagnosis) of type 2 diabetes, obesity, diabetic complications or arteriosclerosis for elucidation of the etiology of type 2 diabetes, obesity, diabetic complications or arteriosclerosis, And human type 2 diabetes, obesity, diabetic complications or compared to normal human liver tissue to assess the risk of suffering from type 2 diabetes, obesity, diabetic complications or arteriosclerosis Measure the expression of type 2 diabetes-related gene and / or obesity-related gene containing nucleotide consisting of the nucleotide sequence of a gene whose expression is increased or attenuated in the liver tissue of arteriosclerosis patients or a nucleotide containing a partial sequence thereof Including reagents for. The reagent is a reagent comprising a nucleotide comprising the nucleotide sequence of the gene or a nucleotide comprising a partial sequence thereof as a probe or primer, and a nucleotide comprising the nucleotide sequence of the gene or a nucleotide comprising a partial sequence thereof as a solid phase. A microarray substrate.

マイクロアレイは、前記遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを適当な基板上に固定化することにより作製することができる。   The microarray can be prepared by immobilizing a nucleotide comprising the base sequence of the gene or a nucleotide containing a partial sequence thereof on an appropriate substrate.

固定基板としては、ガラス板、石英板、シリコンウェハーなどが挙げられる。基板の大きさとしては、例えば3.5mm×5.5mm、18mm×18mm、22mm×75mmなどが挙げられるが、これは基板上のプローブのスポット数やそのスポットの大きさなどに応じて様々に設定することができる。ポリヌクレオチドまたはその断片の固定化方法としては、ヌクレオチドの荷電を利用して、ポリリジン、ポリエチレンイミン、ポリアルキルアミンなどのポリ陽イオンで表面処理した固相担体に静電結合させたり、アミノ基、アルデヒド基、エポキシ基などの官能基を導入した固相表面に、アミノ基、アルデヒド基、SH基、ビオチンなどの官能基を導入したヌクレオチドを共有結合により結合させることもできる。固定化は、アレイ機を用いて行えばよい。   Examples of the fixed substrate include a glass plate, a quartz plate, and a silicon wafer. Examples of the size of the substrate include 3.5 mm × 5.5 mm, 18 mm × 18 mm, 22 mm × 75 mm, etc., which are variously set according to the number of probe spots on the substrate and the size of the spots. be able to. As a method for immobilizing a polynucleotide or a fragment thereof, it is possible to electrostatically bind to a solid phase carrier surface-treated with a polycation such as polylysine, polyethyleneimine, polyalkylamine, etc. A nucleotide having a functional group such as an amino group, an aldehyde group, an SH group, or biotin can be covalently bonded to a solid phase surface into which a functional group such as an aldehyde group or an epoxy group has been introduced. Immobilization may be performed using an array machine.

前記試薬は、HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群、MCR病態関連遺伝子群およびBMI病態関連遺伝子群に属する６２遺伝子の中の少なくとも１種、好ましくは少なくとも２種、さらに好ましくは少なくとも５種、さらに好ましくは少なくとも10種、さらに好ましくは少なくとも20種、さらに好ましくは少なくとも30種、さらに好ましくは全部を含んでいる。また、HbA1c病態関連遺伝子群、HOMA-R病態関連遺伝子群、MCR病態関連遺伝子群およびBMI病態関連遺伝子群のそれぞれの群に属する遺伝子の中から少なくとも１種、好ましくは少なくとも２種、さらに好ましくは５種、さらに好ましくは少なくとも10種、さらに好ましくは全部を含んでいる。   The reagent is at least one of 62 genes belonging to the HbA1c pathological condition related gene group, HOMA-R pathological condition related gene group, MCR pathological condition related gene group and BMI pathological condition related gene group, more preferably at least two It includes five, more preferably at least 10, more preferably at least 20, more preferably at least 30, and more preferably all. In addition, at least one, preferably at least two, more preferably among the genes belonging to each of the HbA1c disease state-related gene group, HOMA-R disease state-related gene group, MCR disease state-related gene group, and BMI disease state-related gene group 5 types, more preferably at least 10 types, more preferably all are included.

上記のように、これらの遺伝子は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子となり得る。従って、本発明の遺伝子および遺伝子を含む試薬は、糖・脂質代謝、糖尿病性合併症、動脈硬化症などの病態を作るキー分子の解析のためのツールとして用い得る。   As described above, these genes can be key molecules for pathological conditions such as sugar / lipid metabolism, diabetic complications, and arteriosclerosis. Therefore, the gene of the present invention and the reagent containing the gene can be used as a tool for analyzing key molecules that cause pathologies such as sugar / lipid metabolism, diabetic complications, and arteriosclerosis.

また、上記試薬を含む２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症の検出（診断薬）、または２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症に罹るリスクを評価するための検出薬も本発明に包含される。   In addition, type 2 diabetes, obesity, diabetic complications or arteriosclerosis detection (diagnostic agent) containing the above reagents, or the risk of suffering from type 2 diabetes, obesity, diabetic complications or arteriosclerosis is evaluated. Detection agents for this are also encompassed by the present invention.

さらに、本発明は、ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病、肥満症、糖尿病性合併症または動脈硬化症患者の肝臓組織で発現が亢進または減弱している遺伝子を用いて２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症の治療薬、または２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症の予防薬をスクリーニングする方法を包含する。例えば、候補薬剤を被験体に投与し、あるいは候補薬剤を前記遺伝子と接触させ、前記遺伝子の発現が亢進させるかまたは減弱させる薬剤を、治療薬または予防薬として選択することができる。   Furthermore, the present invention uses a gene whose expression is increased or decreased in the liver tissue of human type 2 diabetes, obesity, diabetic complications or arteriosclerosis patients as compared with liver tissue of normal humans. It includes a method for screening a therapeutic agent for type 2 diabetes, obesity, diabetic complications or arteriosclerosis, or a prophylactic agent for type 2 diabetes, obesity, diabetic complications or arteriosclerosis. For example, an agent that administers a candidate agent to a subject or makes a candidate agent contact with the gene to increase or decrease the expression of the gene can be selected as a therapeutic or prophylactic agent.

本発明を以下の実施例によって具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。   The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

サンプル
SAGE法を用いた解析をおこなうために、胃癌、胆嚢癌、大腸癌等の悪性腫瘍に対して外科的治療を必要とした、２型糖尿病患者5名、耐糖能正常患者5名から肝組織を得た（表１）。肝組織を肝の癌非浸潤部から外科的に切除し、液体窒素にて速やかに凍結した。 sample
Liver tissue from 5 patients with type 2 diabetes and 5 patients with normal glucose tolerance who needed surgical treatment for malignant tumors such as gastric cancer, gallbladder cancer, colon cancer, etc. to perform analysis using the SAGE method Obtained (Table 1). The liver tissue was surgically excised from the non-infiltrated part of the liver and immediately frozen with liquid nitrogen.

Figure 2006296346
Figure 2006296346

定量的リアルタイムPCR法をおこなうために、２型糖尿病患者21名、耐糖能正常患者11名から肝組織を得た（表２）。経皮的超音波ガイド下肝生検にて肝組織を獲得した後、液体窒素にて速やかに凍結した。   In order to perform quantitative real-time PCR, liver tissue was obtained from 21 patients with type 2 diabetes and 11 patients with normal glucose tolerance (Table 2). Liver tissue was obtained by percutaneous ultrasound-guided liver biopsy, and then quickly frozen in liquid nitrogen.

Figure 2006296346
Figure 2006296346

２型糖尿病群と耐糖能正常群で年齢、BMI、肝機能に有意差はなかった。全症例においてB、C型肝炎関連検査に異常はなかった。糖尿病群症例は、アメリカ糖尿病学会の糖尿病診断及び分類基準に基づいて２型糖尿病と診断した。全症例から書面にてインフォームドコンセントを獲得した。本研究は実験プロトコールについて金沢大学倫理委員会の承認を得たのち、ヘルシンキ宣言に沿って施行した。   There was no significant difference in age, BMI, or liver function between the type 2 diabetes group and normal glucose tolerance group. There were no abnormalities in the tests related to hepatitis B and C in all cases. Diabetes group cases were diagnosed as type 2 diabetes based on diabetes diagnosis and classification criteria of the American Diabetes Association. Informed consent was obtained in writing from all cases. This study was conducted according to the Declaration of Helsinki after obtaining approval from the Kanazawa University Ethics Committee for the experimental protocol.

SAGE法
肝組織から抽出した全RNAをFastTrac mRNA抽出キット（Invitrogen, San Diego, CA）を用いてアデニル化した。各サンプルにつき2.5μgのRNAをSAGE法に用いた。SAGE法のプロトコールは過去の報告に従った（Yamashita T. et al., Biochem Biophys Res Commun 269:110-116, 2000; Yamashita T. et al., Biochem Biophys Res Commun 282:647-654, 2001）。SAGEライブラリーをABI PRISM 377 DNAシーケンサーとBigDyeターミネーターサイクルシーケンスキット（PE Biosystems, Foster city, CA）を用いてシーケンスした。シーケンスしたファイルをSAGE 2000ソフトウエア（www.sagenet.org）を用いて解析した。 SAGE method Total RNA extracted from liver tissue was adenylated using FastTrac mRNA extraction kit (Invitrogen, San Diego, CA). 2.5 μg of RNA for each sample was used in the SAGE method. The protocol of the SAGE method followed a previous report (Yamashita T. et al., Biochem Biophys Res Commun 269: 110-116, 2000; Yamashita T. et al., Biochem Biophys Res Commun 282: 647-654, 2001) . The SAGE library was sequenced using an ABI PRISM 377 DNA sequencer and BigDye terminator cycle sequence kit (PE Biosystems, Foster city, CA). Sequenced files were analyzed using SAGE 2000 software (www.sagenet.org).

定量的リアルタイムPCR法
二重鎖cDNAを定量的リアルタイムPCR法のための鋳型として用いた。この目的のために、ABI Prism 7700シーケンスディテクションシステム（App1ied Biosystems, Foster City, Calif., USA）を使用した。プライマーとTaqManプローブのセットはApplied Biosystems専売のものである（Assays-on-Demand gene expression product）。異なったサンプルにおけるPCRに利用可能なDNA量の変動を補正する目的で、標的配列の遺伝子発現を内因性コントロールであるベータアクチンRNA（TaqMan Control Reagent Kit, Appleid Biosystems）の発現量で標準化した。PCR条件は、50℃2分間および95℃10分間を1サイクル、その後95℃15秒間と60℃1分間を40サイクルとした。 Quantitative real-time PCR method Double-stranded cDNA was used as a template for quantitative real-time PCR method. For this purpose, an ABI Prism 7700 sequence detection system (App1ied Biosystems, Foster City, Calif., USA) was used. Primer and TaqMan probe sets are exclusive to Applied Biosystems (Assays-on-Demand gene expression product). In order to compensate for variations in the amount of DNA available for PCR in different samples, the gene expression of the target sequence was normalized with the expression level of beta actin RNA (TaqMan Control Reagent Kit, Appleid Biosystems), which is an endogenous control. PCR conditions were 50 ° C for 2 minutes and 95 ° C for 10 minutes for one cycle, followed by 95 ° C for 15 seconds and 60 ° C for 1 minute for 40 cycles.

Gene Ontologyによる細胞内局在の推定
Gene Ontology Consortium（http://www.geneontology.org/）の記載に基づき、同定した遺伝子を転写産物の細胞内局在によって分類した。そのなかで、「細胞外」のクラスに分類された遺伝子群を分泌蛋白コード遺伝子としてより詳細に検討した。 Estimation of intracellular localization by Gene Ontology
Based on the description of Gene Ontology Consortium (http://www.geneontology.org/), the identified genes were classified by the intracellular localization of the transcripts. Among them, the genes classified into the “extracellular” class were examined in more detail as secretory protein-coding genes.

HOMA-R
各症例におけるインスリン抵抗性、特に肝臓におけるインスリン抵抗性を評価するために、各症例のHOMA-Rを計算した。HOMA-Rは過去の報告（Matthews DR et al., Diabetologia 28:412-419, 1985）に従い、各症例の空腹時血糖値（mg/dL）X空腹時の血中インスリン濃度μU/ml）/405から計算した。 HOMA-R
In order to assess insulin resistance in each case, especially in the liver, HOMA-R for each case was calculated. HOMA-R is based on past reports (Matthews DR et al., Diabetologia 28: 412-419, 1985). Fasting blood glucose level (mg / dL) X fasting blood insulin concentration μU / ml) / Calculated from 405.

MCR
骨格筋におけるインスリン抵抗性を正確に評価するために、人工膵臓を用いた高インスリン正常血糖下クランプ法（DeFronzo RA et al., Am J Physiol 237:E214-223, 1979）を用いて、Metabolic clearance rate（MCR）を計算した。 MCR
In order to accurately evaluate insulin resistance in skeletal muscle, metabolic clearance using hyperinsulinmic normoglycemic clamp method using artificial pancreas (DeFronzo RA et al., Am J Physiol 237: E214-223, 1979) The rate (MCR) was calculated.

統計学的検定方法
２型糖尿病患者群と耐糖能正常患者群の臨床的特徴の比較はunpaired-t testを用いた。BMI、HOMA-R、MCRと各遺伝子の発現レベルとの関係の解析は線形相関解析でおこなった。いずれもP<0.05を有意とした。 Statistical test method The unpaired-t test was used to compare the clinical characteristics of patients with type 2 diabetes and normal glucose tolerance. The relationship between BMI, HOMA-R, MCR and the expression level of each gene was analyzed by linear correlation analysis. In all cases, P <0.05 was considered significant.

〔結果〕
SAGE解析
SAGE法を用いて、144,901タグ（２型糖尿病患者群44280タグ、耐糖能正常患者群100,621タグ）の遺伝子を同定した。Basic local alignment search tool program（BLAST http://www.ncbi.nlm.nih.gov/BLAST/）を用いてタグ配列から相当遺伝子を解析した結果、２型糖尿病患者群から5221遺伝子、耐糖能正常患者群から6511遺伝子の発見を同定した。Gene Ontology Consortium（http://www. geneontology.org/）の記載を用いて遺伝子を転写産物の細胞内局在別に分類したところ、232遺伝子が“細胞外分泌蛋白”をコードする遺伝子であった。このうちで、２型糖尿病患者群で耐糖能正常患者群に比較して1.5倍以上に発現亢進している63遺伝子、1.5倍以下に発現低下している114遺伝子を同定した。上記の遺伝子について、定量的リアルタイムPCR法を用いて各症例における遺伝子発現量を測定し、BMI、H0MA-R、MCRといった臨床的パラメーターと比較検討した。 〔result〕
SAGE analysis
Using the SAGE method, the genes of 144,901 tags (type 2 diabetes patient group 44280 tag, normal glucose tolerance patient group 100,621 tag) were identified. As a result of analyzing the corresponding gene from the tag sequence using the Basic local alignment search tool program (BLAST http://www.ncbi.nlm.nih.gov/BLAST/), 5221 genes from patients with type 2 diabetes, normal glucose tolerance We identified the discovery of 6511 genes from the patient group. When genes were classified according to the intracellular localization of transcripts using the description of Gene Ontology Consortium (http://www.geneontology.org/), 232 genes were genes encoding “extracellular secreted proteins”. Among these, 63 genes whose expression was increased 1.5 times or more in the type 2 diabetes patient group and 114 genes whose expression was decreased 1.5 times or less were identified as compared with the normal glucose tolerance patient group. For the above genes, the amount of gene expression in each case was measured using quantitative real-time PCR, and compared with clinical parameters such as BMI, H0MA-R, and MCR.

発現レベルとHbAlc値との間に有意な相関を認める遺伝子群の同定
発現レベルとHbA1c値との間に有意な相関を認める14遺伝子を同定した（表３）。これらの遺伝子は、糖代謝を正あるいは負に制御する作用、あるいは高血糖や高インスリン血症、酸化ストレス等を感知して発現が制御されるものと考えられる。これらの中に糖尿病自体、あるいは合併症の病態を作り出している遺伝子が含まれていることが期待される。 Identification of Gene Group Recognizing Significant Correlation between Expression Level and HbAlc Value Fourteen genes having a significant correlation between expression level and HbA1c value were identified (Table 3). The expression of these genes is considered to be controlled by positively or negatively controlling sugar metabolism, or by detecting hyperglycemia, hyperinsulinemia, oxidative stress, or the like. These genes are expected to contain genes that create diabetes itself or complications.

Figure 2006296346
Figure 2006296346

発現レベルとBMIとの聞に有意な相関を認める遺伝子群の同定
発現レベルとBMIとの聞に有意な相関を認める29遺伝子を同定した（表４）。これらの遺伝子は、全身の脂肪蓄積量と関連してその発現が変動していると考えられる。これらの中に、細胞の脂質代謝やエネルギー代謝を調節する遺伝子、あるいはインスリン低抗性に関連した病態を形成する遺伝子が含まれていることが期待される。 Identification of genes that have a significant correlation between expression level and BMI 29 genes that have a significant correlation between expression level and BMI were identified (Table 4). These genes are thought to vary in their expression in relation to systemic fat accumulation. Among these, it is expected that genes that regulate lipid metabolism and energy metabolism of cells, or genes that form pathologies related to insulin resistance.

Figure 2006296346
Figure 2006296346

発現レベルとHOMA-Rとの間に有意な相関を認める遺伝子群の同定
発現レベルとHOMA-Rとの間に有意な相関を認める６遺伝子を同定した（表５）。これらの遺伝子は、肝臓におけるインスリン抵抗性と関連してその発現が変動している、これらの中に、細胞の脂質代謝やエネルギー代謝を調節する遺伝子、あるいはインスリン抵抗性に関連した病態を形成する遺伝子が含まれていることが期待される。 Identification of genes that have a significant correlation between expression level and HOMA-R Six genes that have a significant correlation between expression level and HOMA-R were identified (Table 5). These genes vary in their expression in relation to insulin resistance in the liver, among them genes that regulate cell lipid metabolism and energy metabolism, or pathologies related to insulin resistance Expected to contain genes.

Figure 2006296346
Figure 2006296346

発現レベルとMCRとの間に有意な相関を認める遺伝子群の同定
発現レベルとMCRとの間に有意な相関を認める21遺伝子を同定した（表６）。これらの遺伝子は、骨格筋を代表とする末梢組織のインスリン抵抗性と関連してその発現が変動している。これらの中に、臓器間のインスリンシグナルや糖・脂質の流れを制御する遺伝子、あるいはインスリン低抗性に関連した病態を形成するが含まれていることが期待される。 Identification of Gene Group Recognizing Significant Correlation between Expression Level and MCR Twenty-one genes having a significant correlation between expression level and MCR were identified (Table 6). The expression of these genes varies in association with insulin resistance in peripheral tissues such as skeletal muscle. It is expected that these include genes that control insulin signals and sugar / lipid flow between organs, and those that form pathologies related to insulin resistance.

Figure 2006296346
Figure 2006296346

以上の実施例が示すように、２型糖尿病患者の肝臓で発現が減弱もしくは亢進しており、その発現レベルが血糖コントロール、肥満、肝臓・骨格筋のインスリン低抗性と相関する分泌蛋白コード遺伝子群を同定した。これらの遺伝子にコードされる肝由来分泌蛋白は、細胞内のインスリンシグナル、糖・脂質代謝等に影響を及ぼすと思われ、全身の脂肪蓄積、インスリン低抗性や動脈硬化発症に関連している可能性がある、これらの分泌蛋白の機能を明らかにすることは、２型糖尿病や肥満症の病因解明ならびに新規治療法の開発につながることが期待される。   As shown in the above examples, a secreted protein-encoding gene whose expression is attenuated or enhanced in the liver of type 2 diabetic patients and whose expression level correlates with glycemic control, obesity, and insulin resistance of liver / skeletal muscle Groups were identified. Liver-derived secreted proteins encoded by these genes are thought to affect intracellular insulin signals, sugar / lipid metabolism, etc., and are related to systemic fat accumulation, insulin resistance and atherosclerosis It is expected that elucidating the functions of these secreted proteins may lead to the elucidation of the etiology of type 2 diabetes and obesity and the development of new therapies.

Claims (17)

ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者または肥満症患者の肝臓組織で発現が亢進または減弱している遺伝子であって、分泌タンパク質をコードしている以下の遺伝子からなる群から選択される少なくとも１つの遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを含む２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 A group consisting of the following genes encoding secreted proteins, the expression of which is increased or attenuated in the liver tissue of human type 2 diabetic or obese patients compared to normal human liver tissue A reagent for measuring the expression of a type 2 diabetes-related gene and / or an obesity-related gene comprising a nucleotide comprising a nucleotide sequence of at least one gene selected from or a nucleotide sequence comprising a partial sequence thereof.
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がヒト血中HbA1c値と相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項１記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 At least one gene selected from the group consisting of the following genes whose expression is up- or down-regulated in the liver tissue of a human type 2 diabetes patient, whose up- or down-expression is correlated with human blood HbA1c level: The reagent for measuring the expression of a type 2 diabetes-related gene and / or an obesity-related gene according to claim 1.
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がHOMA-Rと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項１記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with HOMA-R A reagent for measuring the expression of a type 2 diabetes-related gene and / or obesity-related gene according to claim 1.
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がMCRと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項１記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。
(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 The gene whose expression is enhanced or attenuated in liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with MCR: A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to 1.
(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 ヒト肥満症患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がBMIと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項１記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 2. The gene whose expression is enhanced or attenuated in the liver tissue of a human obese patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with BMI: A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene.
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 少なくとも５つの遺伝子を含む請求項１〜５のいずれか１項に記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。   A reagent for measuring the expression of a type 2 diabetes-related gene and / or an obesity-related gene according to any one of claims 1 to 5, comprising at least five genes. ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを固相化したマイクロアレイを含む請求項１〜６のいずれか１項に記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。   A microarray on which a nucleotide comprising a nucleotide sequence of a gene whose expression is enhanced or attenuated in a liver tissue of a human type 2 diabetic patient or a partial sequence thereof is solid-phased compared with a liver tissue of a normal human human A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to any one of claims 1 to 6. ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドをターゲットとしたプローブまたはプライマーを含む請求項１〜６のいずれか１項に記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬。   Probe or primer targeting a nucleotide comprising a nucleotide sequence of a gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient compared to that of a normal human liver or a nucleotide comprising a partial sequence thereof A reagent for measuring the expression of the type 2 diabetes-related gene and / or obesity-related gene according to any one of claims 1 to 6. ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子であって、分泌タンパク質をコードしている以下の遺伝子からなる群から選択される少なくとも１つの遺伝子について、被検体における発現を測定し、該遺伝子の発現が正常人に比較して亢進または減弱している場合に前記被検体が２型糖尿病、肥満症、糖尿病性合併症もしくは動脈硬化症に罹患しているか、または罹患するリスクがあると判断する方法。
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 A gene whose expression is increased or attenuated in the liver tissue of a human type 2 diabetic patient compared to the liver tissue of a normal human subject, and is selected from the group consisting of the following genes encoding secreted proteins For at least one gene, the expression in the subject is measured, and when the expression of the gene is increased or decreased compared to a normal person, the subject has type 2 diabetes, obesity, diabetic complications or arteries. A method of determining that you are suffering from or at risk of suffering from sclerosis.
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(60) C18orf10 chromosome 18 open reading frame 10
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80 ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がヒト血中HbA1c値と相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項９記載の方法。
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen/fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83,SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 At least one gene selected from the group consisting of the following genes whose expression is up- or down-regulated in the liver tissue of a human type 2 diabetes patient, whose up- or down-expression is correlated with human blood HbA1c level: 10. The method of claim 9, wherein
(1) poliovirus receptor
(2) lectin, galactoside-binding, soluble, 8 (galectin 8)
(3) ficolin (collagen / fibrinogen domain containing) 3 (Hakata antigen)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(5) midkine (neurite growth-promoting factor 2)
(6) nucleobindin 2
(7) matrix metalloproteinase 11 (stromelysin 3)
(8) glutathione peroxidase 3 (plasma)
(9) chromosome 14 open reading frame 2
(10) chromosome 14 open reading frame 4
(11) chromosome 10 open reading frame 10
(12) chromosome 6 open reading frame 74
(13) chromosome 9 open reading frame 83, SNF7 domain containing 2 (SNF7DC2), mRNA
(14) chromosome 8 open reading frame 1 ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がHOMA-Rと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項９記載の方法。
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) The gene whose expression is enhanced or attenuated in the liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with HOMA-R The method of claim 9.
(42) thrombospondin 1
(43) cathepsin S
(44) paraoxonase 1
(45) DEFB1 defensin beta 1
(46) MAP2K2 mitogen activated protein kinase kinase 2
(47) phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がMCRと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項９記載の方法。
(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 The gene whose expression is enhanced or attenuated in liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with MCR: 9. The method according to 9.
(42) thrombospondin 1
(48) IGFBP1 insulin like growth factor binding protein 1
(49) sulfatase 2
(50) wingless type MMTV integration site family member 5B
(51) ADAMTS1 a disintegrin like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1
(52) selenoprotein P, plasma, 1n
(53) chondroadherin
(54) decorin
(55) cathepsin S
(56) lipopolysaccharide binding protein
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(57) SPARC-like 1 (mast9, hevin)
(58) leucine-rich alpha-2-glycoprotein 1
(59) chromosome 14 open reading frame 100
(35) chromosome 14 open reading frame 123
(9) chromosome 14 open reading frame 2
(60) C18orf10 chromosome 18 open reading frame 10
(37) chromosome 5 open reading frame 13
(61) chromosome 6 open reading frame 79
(62) C6orf80 chromosome 6 open reading frame 80
(38) chromosome 9 open reading frame 10 ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子が、発現の亢進または減弱がBMIと相関している以下の遺伝子からなる群から選択される少なくとも１つの遺伝子である請求項９記載の方法。
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (C-C motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 The gene whose expression is enhanced or attenuated in liver tissue of a human type 2 diabetes patient is at least one gene selected from the group consisting of the following genes whose expression is correlated with BMI: 9. The method according to 9.
(15) bone morphogenetic protein 2
(16) leukocyte cell-derived chemotaxin 2
(17) adipose differentiation-related protein
(18) Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
(19) serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1
(20) GNAS complex locus
(21) AHSG alpha 2 HS glycoprotein
(22) chemokine (CC motif) ligand 16
(23) afamin
(24) LTBP1 latent transforming growth factor beta binding protein 1
(25) complement component 4 binding protein, alpha
(26) lysozyme (renal amyloidosis)
(4) MMP24 matrix metalloproteinase 24 (membrane inserted)
(27) prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)
(28) histidine-rich glycoprotein
(29) FST follistatin
(30) glypican 3
(31) glycosylphosphatidylinositol specific phospholipase D1
(32) GDF15 growth differentiation factor 15
(33) SPINT2 serine protease inhibitor Kunitz type 2
(34) TNFRSF1A tumor necrosis factor receptor superfamily member 1A
(35) chromosome 14 open reading frame 123
(14) chromosome 8 open reading frame 1
(36) chromosome 14 open reading frame 32
(37) chromosome 5 open reading frame 13
(38) chromosome 9 open reading frame 10
(39) C10orf107 chromosome 10 open reading frame 107
(40) C1orf38 chromosome 1 open reading frame 38
(41) C10orf58 chromosome 10 open reading frame 58 少なくとも５つの遺伝子について被検体における発現を測定する請求項９〜１３のいずれか１項に記載の方法。   The method according to any one of claims 9 to 13, wherein expression in a subject is measured for at least five genes. ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドを固相化したマイクロアレイを用いる請求項９〜１４のいずれか１項に記載の方法。   A microarray on which a nucleotide comprising a nucleotide sequence of a gene whose expression is enhanced or attenuated in a liver tissue of a human type 2 diabetic patient or a partial sequence thereof is solid-phased compared with a liver tissue of a normal human human The method according to any one of claims 9 to 14, which is used. ヒト正常人の肝臓組織と比較して、ヒト２型糖尿病患者の肝臓組織で発現が亢進または減弱している遺伝子の塩基配列からなるヌクレオチドまたはその一部配列を含むヌクレオチドをターゲットとしたリアルタイムPCRにより該遺伝子の発現を解析することを含む請求項９〜１４のいずれか１項に記載の方法。   Real-time PCR targeting nucleotides consisting of the nucleotide sequence of a gene whose expression is enhanced or attenuated in the liver tissue of human type 2 diabetic patients compared to that of normal human liver, or a nucleotide containing a partial sequence thereof. The method according to any one of claims 9 to 14, comprising analyzing the expression of the gene. 請求項１〜８のいずれか１項に記載の２型糖尿病関連遺伝子および／または肥満症関連遺伝子の発現を測定するための試薬を含む２型糖尿病、肥満症、糖尿病性合併症および動脈硬化症の検出またはリスク判定のためのキット。   Type 2 diabetes, obesity, diabetic complications and arteriosclerosis comprising a reagent for measuring the expression of the type 2 diabetes related gene and / or obesity related gene according to any one of claims 1 to 8 Kit for detection or risk assessment.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011149057A1 (en) * 2010-05-27 2011-12-01 国立大学法人 東京大学 Methods for detection of risk of obesity and risk of onset of diabetes
CN101561440B (en) * 2008-04-16 2014-03-05 中国科学院上海生命科学研究院 Application of fiber gelatinized protein 3

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016188761A (en) * 2013-08-23 2016-11-04 国立研究開発法人国立国際医療研究センター Method and kit for detecting onset of diabetic nephropathy or onset risk
WO2016123163A2 (en) 2015-01-27 2016-08-04 Kardiatonos, Inc. Biomarkers of vascular disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JPN6010052749, Ｄｉａｂｅｔｏｌｏｇｉａ， ２００４， ｖｏｌ．４７， ｎｏ．４， ｐ．６３８−６４７ *

Cited By (4)

* Cited by examiner, † Cited by third party
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CN101561440B (en) * 2008-04-16 2014-03-05 中国科学院上海生命科学研究院 Application of fiber gelatinized protein 3
WO2011149057A1 (en) * 2010-05-27 2011-12-01 国立大学法人 東京大学 Methods for detection of risk of obesity and risk of onset of diabetes
JP5422799B2 (en) * 2010-05-27 2014-02-19 国立大学法人 東京大学 Methods for detecting obesity risk and diabetes risk
EP2921562A1 (en) 2010-05-27 2015-09-23 The University of Tokyo Method of detecting obesity risk or diabetes onset risk

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