Identification of type 2 diabetes susceptibility genes in the Japanese population by genome mapping and candidate gene approach and functional analysis

通过基因组作图、候选基因方法和功能分析鉴定日本人群中 2 型糖尿病易感基因

• 批准号: 14013008
• 负责人: KADOWAKI Takashi
• 金额: $ 17.02万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14013008/
• 关键词: SNP; Haplotype; diabetes; affected sib pair; adiponectin; 相関解析; 連鎖不平衡; インスリン抵抗性; 2型糖尿病; アディポネクチン受容体; 脂肪細胞; 個人情報匿名化; 罹患同胞対法; 全ゲノムスキャン; 一塩基多型; 動脈硬化

We have mapped type 2 diabetes susceptibility genes to the 9 chromosomal regions 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 9p, llp13-p12, 15q13-q21, and 20q12-q13) in the Japanese population. In 3q26-q28, the gene encoding adiponectin which is adipocyte-derived insulin sensitizing hormone, is located. We found that SNP276 in the adiponectin gene was associated with plasma level of adiponectin, insulin resistance, and risk of type 2 diabetes, suggesting that the adiponectin gene is a type 2 diabetes susceptibility gene. In1q36-32, the AMPKa2 subunit gene is located ant we found that polymorphism in the AMPKa2 subunit gene is associated with insulin resistance and type 2 diabetes. In 20q12-q13 we found we found verystrong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene, although none of the individual polymorphisms examined showed any significant association with type 2 diabetes. In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as yet unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene directly influencing the susceptibility to type 2 diabetes. We are performing association studies using dense map of SNP in the remaining 6 chromosomal regions we have mapped to identify type 2 diabetes susceptibility genes in the Japanese population.

我们已将2型糖尿病易感基因定位于日本人群中的9个染色体区域(1p36-p32、2q34、3q26-q28、6p23、7p22-p21、9p、11p13-p12、15q13-q21和20q12-q13)。在3q26-q28中，定位了脂肪细胞来源的胰岛素增敏激素脂联素的编码基因。我们发现脂联素基因中的SNP276与血浆脂联素水平、胰岛素抵抗和2型糖尿病的风险相关，提示脂联素基因是2型糖尿病的易感基因。在1q36-32中定位了AMPKa2亚基基因，我们发现AMPKa2亚基基因的多态性与胰岛素抵抗和2型糖尿病有关。在20q12-q13，我们发现了HNF4a基因P2启动子区域的两个多态组成的单倍型与2型糖尿病之间存在关联的非常有力的证据，尽管所研究的个体多态与2型糖尿病没有任何显著的关联。而非P2启动子区的单倍型与2型糖尿病无关联，提示2型糖尿病易感基因定位于HNF4a基因的P2启动子区域。分析结果表明，HNF4a基因可能是不同种族人群共有的2型糖尿病易感基因。研究还表明，HNF4a基因的P2启动子区可能存在一种尚未确定但具有功能性的多态性，直接影响2型糖尿病的易感性。我们正在进行关联研究，利用我们已绘制的其余6个染色体区域中的SNP密集图谱来识别日本人群中的2型糖尿病易感基因。

项目成果

原 一雄, 門脇 孝: "2型糖尿病のゲノム解析と疾患感受性遺伝子"実験医学. 21. 5-10 (2002)

Kazuo Hara、Takashi Kadowaki：“2 型糖尿病和疾病易感基因的基因组分析”《实验医学》21. 5-10 (2002)。

The role of PPAR gamma in high-fat diet-induced obesity and insulin resistance.

PPAR γ 在高脂饮食引起的肥胖和胰岛素抵抗中的作用。

• 发表时间: 2002
• 期刊: J Diabetes Complications 16
• 作者: Kadowaki T

The Pro12→Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population : possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.

PPAR-γ 中的 Pro12→Ala 替代与普通人群对糖尿病发展的抵抗力相关：可能与 2 型糖尿病患者的胰岛素分泌受损有关。

• 发表时间: 2002
• 期刊: Diabetes 50
• 作者: Mori H;Ikegami H;Kawaguchi Y;Seino S;Yokoi N;Takeda J;Inoue I;Seino Y;Yasuda K;Hanafusa T;Yamagata K;Awata T;Kadowaki T;Hara K;Yamada N;Gotoda T;Iwasaki N;Iwamoto Y;Sanke T;Nanjo K;Oka Y;Matsutani A;Maeda E;Kasuga M.
• 通讯作者: Kasuga M.

2型糖尿病の診断又は検査方法

2型糖尿病的诊断或检测方法

• 发表时间: 2002

Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes

• DOI: 10.1007/s00125-005-1806-3
• 发表时间: 2005-07-01
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Hara, K;Horikoshi, M;Kadowaki, T
• 通讯作者: Kadowaki, T