JP2004049033A - Method for diagnosing or examining type 2 diabetes mellitus - Google Patents
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【0001】
【発明の属する技術分野】
本発明は、ヒトアディポネクチン遺伝子の1塩基多型を同定することによる2型糖尿病の診断又は検査方法及び診断薬に関する。
【0002】
【従来の技術及び発明が解決しようとする課題】
2型糖尿病は、遺伝的素因を背景にして、インスリン分泌異常やインスリン抵抗性を有するヒトに対して、高脂肪食の摂取、運動不足、ストレス、肥満等の発症因子がかかったときに発症する、いわゆる多因病である。このように2型糖尿病は、1型糖尿病とは原因が大きく異なり、その診断及び治療は極めて困難である。
【0003】
特に我が国では、1型糖尿病に比べて2型糖尿病が多く、その診断法及び治療法の確立が望まれている。
従って、本発明は、2型糖尿病の新たな診断及び検査方法を提供することを目的とする。
【0004】
【課題を解決するための手段】
最近の研究により、アディポネクチンの発現低下又は欠乏は、肥満インスリン抵抗性の原因であり、ひいては肥満及び2型糖尿病の原因であることが判明している(T. Yamauchi et al, Nature Medicine, Vol. 7, No.8(2001))。しかし、アディポネクチン遺伝子の1塩基多型と2型糖尿病との関係に関しては未だ報告されていない。
【0005】
そこで本発明者は、アディポネクチン遺伝子の1塩基多型に着目し、種々検討したところ、アディポネクチン遺伝子の276番の1塩基多型(SNP276)が、2型糖尿病、インスリン抵抗性及び血中アディポネクチン値と高い相関性を有し、当該SNP276を同定すれば2型糖尿病、特にインスリン抵抗性を伴う2型糖尿病の診断に有用であることを見出し、本発明を完成するに至った。
【0006】
すなわち、本発明は、ヒトアディポネクチン遺伝子の276番の1塩基多型を同定することを特徴とする2型糖尿病の診断又は検査方法を提供するものである。
【0007】
また、本発明は、ヒトアディポネクチン遺伝子の276番の1塩基多型を同定できる塩基長を有するポリヌクレオチドからなるプライマーを提供するものである。
また、本発明は、当該プライマーを含有することを特徴とする2型糖尿病診断薬を提供するものである。
【0008】
【発明の実施の形態】
ヒトアディポネクチン遺伝子は、既にクローニングされており[Maeda, K et al, Biochem. Biophys. Res. Commun. 221, 286−296(1996)、Nakano, Y. et al,J. Biochem. (Tokyo)120, 802−812(1996)]、その塩基配列も知られている(NCBI Accession No. NT−005962)。
【0009】
本発明は、ヒトアディポネクチン遺伝子の276番の1塩基多型(以下、「SNP276」という)を同定して、2型糖尿病を診断又は検査するものである。後記実施例に示すように、2型糖尿病患者及び糖代謝正常者由来のDNAを用いてSNPスクリーニングを行った結果、10個の比較的頻度の高いSNPを同定した(表1)。そのうち、SNP276(G/G、G/T及びT/T)においては、SNP276G/G遺伝子型保持者は、T/T型遺伝子保持者に比べて有意に2型糖尿病発症リストが高いこと、インスリン抵抗性が高いこと及び血中アディポネクチン値が低いことが判明した。従って、当該SNP276を同定すれば、2型糖尿病が診断又は検査でき、インスリン抵抗性を伴う2型糖尿病であるか否かも診断又は検査できる。配列番号1にSNP276G型の1〜1410番の塩基配列を、配列番号2にSNP276T型の1〜1410番の塩基配列を示す。
【0010】
本発明の診断又は検査方法に用いる検体としては、遺伝子含有体液又は組織であればよいが、血液、汗、尿、スワブ(口腔内、鼻腔内、咽喉内等)、毛髪、糞便等が挙げられ、特に血液が好ましい。
【0011】
SNP276の同定法としては、直接シーケンス法、プライマーエクステンション法、PCR法が挙げられる。PCR法としては、ASA法(Allele−specific amplification)、PASA法(PCR amplification of specific alleles)、ASP法(allele−specific RCR)、ARMS法(amplification refractory mutation system)、ASO(allele−specific oligonucleotide)ハイブリダイゼーション法、RCR−RFLP(PCR restriction fragment length polymorphism)等が挙げられるが、このうち特に直接シーケンス法が好ましい。
【0012】
直接シーケンス法やPCR法を用いるSNP276の同定に用いられるプライマーとしては、当該SNP276を含むポリヌクレオチドが増幅されるような塩基長、例えば12塩基長以上、好ましくは12〜30塩基長のプライマーであればよいが、下記の配列を有するプライマーセットが望ましい。
【0013】
5′−AGAAAGCAGCTCCTAGAAGT−3′(配列番号3)
5′−GGCACCATCTACACTCATCC−3′(配列番号4)
【0014】
本発明の診断薬には、上記プライマーを含み、所望によりPCRに必要な緩衝液等が含まれる。
【0015】
【実施例】
次に実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。
【0016】
A.方法
(対象者)
▲1▼60歳以上、▲2▼糖尿病の家族歴を持たない、▲3▼HbAlcが5.8%未満の3条件を満たす日本人糖代謝正常者480名並びに、WHOの基準に合致した日本人2型糖尿病患者384名から書面によるインフォームドコンセントを得て採血を行いDNAを抽出した。また本研究は東京大学大学院医学系研究科ヒトゲノム・遺伝子解析研究に関する倫理審査委員会の承認を受けている。
【0017】
(SNPスクリーニング)
30名の2型糖尿病患者由来のDNAを利用し(80%の件出力でアリル頻度が0.026以上のSNPを同定可能)、直接シーケンス法によりアディポネクチン遺伝子を含む16kbの染色体領域についてSNPのスクリーニングを行った。
【0018】
(SNPタイピング)
同定したSNPについて2型糖尿病384名、糖代謝正常者480名を対象に直接シーケンス法あるいはPrimer Extension法によって遺伝子型を決定した。直接シーケンス法はBigDyeTerminator(Applied Biosystem社製)を用い、PRISM 3100 Genetic Analyzer(Applied Biosystem社製)によって泳動・検出を行った。Primer Extension法はSnaPshot(Applied Biosystem社製)を用いPRISM 3100 GeneticAnalyzer(Applied Biosystem社製)によって泳動・検出を行った。
【0019】
(生化学的検討)
インスリン抵抗性の評価はHOMA(homeostasis model assessment)の指標(インスリン抵抗性指標=((空腹時血糖値(mmol/L)×空腹時インスリン値(μU/mL))/22.5)を使用した。
【0020】
(統計学的検討)
ハプロタイプの頻度推定はEHソフトウェア(ftp://linkage. rockefeller. edu/software/eh)を使用した。各SNPの遺伝子型あるいはアリル頻度についてχ2検定によって糖尿病群と非糖尿病群で差があるか検定を行った。
【0021】
B.結果
(1)アディポネクチン遺伝子新規SNPの同定
計10個の比較的頻度の高い多型を同定した。全てのSNPについてHardy−Weinberg平衡にあった。また、頻度の低い(アリル頻度が1%以下)G84R、I164T、R221S、H241Pを同定した。頻度の高い多型は、次のとおりである。
SNP−11414(A−G)、SNP−11379(G−A)、SNP−11365(C−G)、SNP−4034(A−C)、SNP−3964(A−G)、SPN45(T−G)、SNP276(G−T)、SNP349(A−G)、SNP712(A−G)、SNP2019(A欠損−A挿入)。
アディポネクチン遺伝子におけるこれらの多型の存在部位を図1に示す。
【0022】
(2)アディポネクチン遺伝子SNPと2型糖尿病との相関
結果を表1に示す。
【0023】
【表1】
【0024】
新規に同定した比較的頻度の高い10個のSNPのうちSNP45(p=0.01)及びSNP276(p=0.007)と2型糖尿病との間に有意な相関を認めた。SNP45についてはG/G、G/T遺伝子型保持者はT/T遺伝子型保持者に比してそれぞれオッズ比で1.41(95%信頼区間1.06−1.88)、1.70(95%信頼区間1.09−2.65)、SNP276に関してはG/G遺伝子型保持者はT/T遺伝子型保持者に比して2.16(95%信頼区間1.22−3.95)と2型糖尿病発症リスクの有意な上昇を認めた。
【0025】
(3)アディポネクチン遺伝子SNPとインスリン抵抗性との相関
アディポネクチンはインスリン感受性物質であることからインスリン抵抗性とSNPとの関連を検討した。2型糖尿病発症リスクが上昇しているSNP276G/G遺伝子型保持者はT/T遺伝子型保持者に比してHOMAの指標が有意に高値(G/G:1.61±0.05, G/T:1.45±0.05, T/T:1.19±0.12, P=0.002)でインスリン抵抗性が上昇していた(図2)。SNP45とインスリン抵抗性指標との間には相関を認めなかった(G/G:1.56±0.11, G/T:1.48±0.06, T/T:1.52±0.05, P=0.787)。
【0026】
(4)アディポネクチン遺伝子SNPと血中アディポネクチン値との相関
SNP276の遺伝子型によってアディポネクチン遺伝子の発現が変化し血中アディポネクチン値に差があるかどうか検討を行った。これまでアディポネクチン値は肥満によって低下することが報告されているため、BMIによって3群に層別化した後SNP276と血中アディポネクチン値との相関を検討した。BMIが26.7以上の群において、2型糖尿病発症リスクが上昇しインスリン抵抗性が高いG/G遺伝子型保持者はT/T遺伝子型保持者に比して血中アディポネクチン値が有意に低いことが明らかとなった(G/G:10.4±0.85, G/T:13.7±0.87, T/T:16.6±2.24μg/mL, P=0.01)(図3)。
【0027】
以上よりSNP276はアディポネクチン低値を介してインスリン抵抗性を惹起し2型糖尿病の発症リスクを上昇させていると考えられた。
【0028】
【発明の効果】
本発明によれば、日本人に特に多い2型糖尿病及びその発症リスクが的確に診断又は検査することができる。また、インスリン抵抗性を伴う2型糖尿病及びその発症リスクが的確に診断できることから、その治療手段の選択も容易となる。
【0029】
【配列表】
【図面の簡単な説明】
【図1】アディポネクチン遺伝子のゲノム構造と多型の存在位置を示す図である。
【図2】SNP276遺伝子型とインスリン抵抗性との関係を示す図である。
【図3】BMIの群別におけるSNP遺伝子型と血中アディポネクチン値との関係を示す図である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for diagnosing or testing type 2 diabetes by identifying a single nucleotide polymorphism in the human adiponectin gene, and a diagnostic agent.
[0002]
Problems to be solved by the prior art and the invention
Type 2 diabetes develops when humans with abnormal insulin secretion or insulin resistance are exposed to high-fat diet, lack of exercise, stress, obesity, and other factors due to genetic predisposition. This is a so-called multifactorial disease. As described above, type 2 diabetes has a significantly different cause from
[0003]
In Japan, in particular, type 2 diabetes is more common than
Therefore, an object of the present invention is to provide a new diagnosis and test method for type 2 diabetes.
[0004]
[Means for Solving the Problems]
Recent studies have shown that reduced expression or deficiency of adiponectin is responsible for obesity insulin resistance, and thus for obesity and type 2 diabetes (T. Yamauchi et al, Nature Medicine, Vol. 7, No. 8 (2001)). However, the relationship between the single nucleotide polymorphism of the adiponectin gene and type 2 diabetes has not yet been reported.
[0005]
Therefore, the present inventor focused on the single nucleotide polymorphism of the adiponectin gene and made various studies. As a result, the single nucleotide polymorphism at position 276 of the adiponectin gene (SNP276) was found to be associated with type 2 diabetes, insulin resistance and blood adiponectin level. The inventors have found that the SNP 276 has high correlation and is useful for diagnosing type 2 diabetes, particularly type 2 diabetes associated with insulin resistance, and has completed the present invention.
[0006]
That is, the present invention provides a method for diagnosing or testing type 2 diabetes, comprising identifying the single nucleotide polymorphism at position 276 of the human adiponectin gene.
[0007]
The present invention also provides a primer comprising a polynucleotide having a nucleotide length capable of identifying a single nucleotide polymorphism at position 276 of the human adiponectin gene.
The present invention also provides a diagnostic agent for type 2 diabetes, which comprises the primer.
[0008]
BEST MODE FOR CARRYING OUT THE INVENTION
The human adiponectin gene has been cloned [Maeda, K et al, Biochem. Biophys. Res. Commun. 221, 286-296 (1996); Nakano, Y .; et al, J.A. Biochem. (Tokyo) 120, 802-812 (1996)], and its base sequence is also known (NCBI Accession No. NT-005962).
[0009]
The present invention identifies a single nucleotide polymorphism at position 276 of the human adiponectin gene (hereinafter referred to as “SNP276”) and diagnoses or tests type 2 diabetes. As shown in Examples below, as a result of performing SNP screening using DNAs derived from patients with type 2 diabetes and normal glucose metabolism, ten relatively frequently occurring SNPs were identified (Table 1). Among them, in SNP276 (G / G, G / T and T / T), the SNP276G / G genotype holder had a significantly higher type 2 diabetes incidence list than the T / T type holder, and insulin High resistance and low blood adiponectin levels were found. Therefore, if the SNP 276 is identified, type 2 diabetes can be diagnosed or tested, and whether or not it is type 2 diabetes with insulin resistance can be diagnosed or tested. SEQ ID NO: 1 shows the nucleotide sequence of Nos. 1-1410 of SNP276G type, and SEQ ID NO: 2 shows the nucleotide sequence of No. 1-1410 of SNP276T type.
[0010]
The specimen used in the diagnosis or test method of the present invention may be a gene-containing body fluid or tissue, and examples thereof include blood, sweat, urine, swab (in the oral cavity, in the nasal cavity, in the throat), hair, feces, and the like. Especially preferred is blood.
[0011]
Examples of the identification method of SNP276 include a direct sequencing method, a primer extension method, and a PCR method. As the PCR method, an ASA method (Allele-specific amplification), a PASA method (PCR amplification of specific alleles), an ASP method (allele-specific RCR), an ARMS method (amplification reference-amplification radiography), Examples include a hybridization method and RCR-RFLP (PCR restriction fragment length polymorphism). Among them, the direct sequence method is particularly preferable.
[0012]
As a primer used for identification of SNP 276 using the direct sequence method or the PCR method, a primer having a base length such that a polynucleotide containing the SNP 276 is amplified, for example, a primer having a length of 12 bases or more, preferably 12 to 30 bases is used. However, a primer set having the following sequence is desirable.
[0013]
5'-AGAAAGCAGCTCCTAGAAGT-3 '(SEQ ID NO: 3)
5'-GGCACCCATCTACACTCATCC-3 '(SEQ ID NO: 4)
[0014]
The diagnostic agent of the present invention contains the above-mentioned primers and, if desired, a buffer solution and the like necessary for PCR.
[0015]
【Example】
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
[0016]
A. Method (target person)
(1) over 60 years old, (2) no family history of diabetes, (3) 480 Japanese people with normal glucose metabolism who meet the three conditions of less than 5.8% HbAlc, and Japan that meets the WHO criteria Informed consent was obtained from 384 human type 2 diabetic patients, blood was collected, and DNA was extracted. This study has also been approved by the Ethics Review Committee on Human Genome and Gene Analysis Research, Graduate School of Medicine, The University of Tokyo.
[0017]
(SNP screening)
Screening of SNP for 16 kb chromosomal region containing adiponectin gene by direct sequencing using DNA from 30 type 2 diabetic patients (80% or more output can identify SNPs with an allele frequency of 0.026 or more) Was done.
[0018]
(SNP typing)
The genotype of the identified SNP was determined by direct sequencing or Primer Extension for 384 type 2 diabetes patients and 480 normal glucose metabolizers. In the direct sequence method, BigDyeTerminator (manufactured by Applied Biosystem) was used, and electrophoresis and detection were carried out using a PRISM 3100 Genetic Analyzer (manufactured by Applied Biosystem). In the Primer Extension method, electrophoresis and detection were carried out using a PRISM 3100 Genetic Analyzer (manufactured by Applied Biosystem) using SnaPshot (manufactured by Applied Biosystem).
[0019]
(Biochemical examination)
For the evaluation of insulin resistance, an index of HOMA (homeostasis model assessment) (insulin resistance index = ((fasting blood glucose level (mmol / L) × fasting insulin level (μU / mL)) / 22.5)) was used. .
[0020]
(Statistical examination)
The haplotype frequency was estimated using EH software (ftp: // linkage. Rockefuller.edu/software/eh). The chi 2 test for genotype or allele frequency of each SNP were assayed whether there is a difference in the diabetic group and non-diabetic group.
[0021]
B. Results (1) Identification of a novel adiponectin gene novel SNP A total of 10 relatively frequent polymorphisms were identified. Hardy-Weinberg equilibrium was attained for all SNPs. In addition, G84R, I164T, R221S, and H241P with low frequency (allele frequency is 1% or less) were identified. Frequent polymorphisms are as follows:
SNP-11414 (AG), SNP-11379 (GA), SNP-11365 (CG), SNP-4034 (AC), SNP-3964 (AG), SPN45 (TG ), SNP276 (GT), SNP349 (AG), SNP712 (AG), SNP2019 (A deletion-A insertion).
The location of these polymorphisms in the adiponectin gene is shown in FIG.
[0022]
(2) Table 1 shows the results of the correlation between the adiponectin gene SNP and type 2 diabetes.
[0023]
[Table 1]
[0024]
Significant correlation was found between SNP45 (p = 0.01) and SNP276 (p = 0.007) among the 10 newly identified relatively frequent SNPs and type 2 diabetes. For SNP45, G / G and G / T genotype holders had an odds ratio of 1.41 (95% confidence interval 1.06-1.88) and 1.70, respectively, compared to T / T genotype holders. (95% CI 1.09-2.65), and for SNP276, G / G genotype holders were 2.16 (95% CI 1.22-3. 95) and a significant increase in the risk of developing type 2 diabetes.
[0025]
(3) Correlation between adiponectin gene SNP and insulin resistance Since adiponectin is an insulin sensitive substance, the relationship between insulin resistance and SNP was examined. SNP276G / G genotype holders with an increased risk of developing type 2 diabetes have significantly higher HOMA indices (G / G: 1.61 ± 0.05, G) than T / T genotype holders. / T: 1.45 ± 0.05, T / T: 1.19 ± 0.12, P = 0.002), indicating an increase in insulin resistance (FIG. 2). No correlation was observed between SNP45 and the insulin resistance index (G / G: 1.56 ± 0.11, G / T: 1.48 ± 0.06, T / T: 1.52 ± 0). .05, P = 0.787).
[0026]
(4) Correlation between adiponectin gene SNP and blood adiponectin level It was examined whether the expression of the adiponectin gene changes depending on the genotype of SNP276 and there is a difference in the blood adiponectin level. It has been reported that adiponectin levels are decreased by obesity. Therefore, after stratification into three groups by BMI, the correlation between SNP276 and blood adiponectin levels was examined. In the group having a BMI of 26.7 or more, G / G genotype carriers who have an increased risk of developing type 2 diabetes and have high insulin resistance have significantly lower blood adiponectin levels than T / T genotype carriers. (G / G: 10.4 ± 0.85, G / T: 13.7 ± 0.87, T / T: 16.6 ± 2.24 μg / mL, P = 0.01 ) (FIG. 3).
[0027]
From the above, it was considered that SNP276 caused insulin resistance via a low adiponectin level and increased the risk of developing type 2 diabetes.
[0028]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the type 2 diabetes and the onset risk which are especially common among Japanese can be diagnosed or tested accurately. In addition, since type 2 diabetes with insulin resistance and the risk of its onset can be accurately diagnosed, it is easy to select a treatment means therefor.
[0029]
[Sequence list]
[Brief description of the drawings]
FIG. 1 shows the genomic structure of the adiponectin gene and the locations of polymorphisms.
FIG. 2 shows the relationship between SNP276 genotype and insulin resistance.
FIG. 3 is a diagram showing the relationship between SNP genotype and blood adiponectin level in each BMI group.
Claims (7)
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006064457A (en) * | 2004-08-25 | 2006-03-09 | Yutaka Sasagawa | Method for determining diabetes and saccharometabolism abnormality |
WO2007032496A1 (en) * | 2005-09-16 | 2007-03-22 | The University Of Tokushima | Method for determination of risk of type 2 diabetes |
-
2002
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2006064457A (en) * | 2004-08-25 | 2006-03-09 | Yutaka Sasagawa | Method for determining diabetes and saccharometabolism abnormality |
JP4533042B2 (en) * | 2004-08-25 | 2010-08-25 | 裕 笹川 | How to determine diabetes and abnormal glucose metabolism |
WO2007032496A1 (en) * | 2005-09-16 | 2007-03-22 | The University Of Tokushima | Method for determination of risk of type 2 diabetes |
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