CLONING OF SUSCEPTIBILITY GENES FOR NON-INSULIN-DEPENDENT DIABETES MELLITUS BY A NOVEL STRATEGY

通过新策略克隆非胰岛素依赖型糖尿病易感基因

• 批准号: 09470220
• 负责人: IKEGAMI Hiroshi
• 金额: $ 5.5万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470220/
• 关键词: MULTIFACTORIAL DISEASE; GENETICS; DIABETES MELLITUS; SUSCEPTIBILITY

Unlike monogenic diseases, classical linkage analysis is not feasible and therefore a novel strategy is required for genetic dissection of multifactorial diseases such as diabetes mellitus. In this study we constructed a novel strategy for genetic dissection for multifactorial diseases in general and diabetes mellitus in particular.For genetic dissection of type 2 diabetes with low Xs values, methods with enough power are required. To increase the power of genetic analysis, we newly eatablished meta-analysis for association studies between genotypes and phenotypes, including quantitative traits. By using this method, we showes significant association between insertion/deletion polymorphism of the ACE gene and susuceptibility to diabetic nephropathy in more than 5000 subjects, and between a quantiative phenotype, body mass index, and mutation in beta 3 adrenergic receptor gene in more than 9000 subjects.To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type 1 diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (QTL) mapping in F2 mice in crosses of NSY with contsol C3H/He mice mapped at least 3 QTL (Nidd1, NIdd2, NIdd3) on mouse chromosomes 11, 14 and 6. Nidd1 appears to affect glucose tolerance through imapired insulin secretion, whereas Nidd2 through insulin resistance. Nidd3 singnificantly affects insulin resistance and abdominal fat accumulation as well as glucose tolerance. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.

与单基因疾病不同，经典的连锁分析是不可行的，因此需要一种新的策略来分析糖尿病等多因素疾病的遗传。在这项研究中，我们构建了一种新的多因素疾病尤其是糖尿病的基因解剖策略，对于低Xs值的2型糖尿病的基因解剖，需要有足够强大的方法。为了增加遗传分析的能力，我们新建立了Meta分析，用于研究基因型和表型之间的关联，包括数量性状。通过使用这种方法，我们在5000多名受试者中发现了ACE基因的插入/缺失多态与糖尿病肾病易感性之间的显著关联，在9000多名受试者中显示了量化表型、体重指数和β3肾上腺素能受体基因突变之间的显著关联。为了使基因分析更简单，我们使用了糖尿病的近交系动物模型(1型糖尿病的NOD小鼠和2型糖尿病的NSY小鼠)。在NSY与对照C3H/He小鼠杂交的F2小鼠中，在11、14和6号染色体上至少定位了3个QTL(Nidd1、NIdd2、NIdd3)。Nidd1可能通过影响胰岛素分泌而影响糖耐量，而Nidd2可能通过胰岛素抵抗影响糖耐量。NID3显著影响胰岛素抵抗、腹部脂肪堆积和糖耐量。这些基因座的经济株系和同源株系目前正在进行进一步的定位和功能分析。

项目成果

Fujisawa T,Ikegami H,Kawaguchi Y,Hamada Y,Ueda H,Shintani M,Fukuda M,Ogihara T: "Meta- analysis of the association of Insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy." Diabetologia. 41. 47-

Fujisawa T、Ikegami H、Kawaguchi Y、Hamada Y、Ueda H、Shintani M、Fukuda M、Ogihara T：“血管紧张素 I 转换酶基因插入/缺失多态性与糖尿病肾病和视网膜病变关联的荟萃分析。”

Hotta M,Tashiro F,Ikegami H,Niwa H,Ogihara T,Yodoi J,Miyazaki J-I: "Pancreatic beta-cell-specific expression of thioredoxin, an antioxidative and anti-apoptotic protein, prevents autoimmune and strptozotocin-induced diabetes." J Exp Med. 188. 1445-1451 (1

Hotta M、Tashiro F、Ikegami H、Niwa H、Ogihara T、Yodoi J、Miyazaki J-I：“硫氧还蛋白（一种抗氧化和抗凋亡蛋白）的胰腺 β 细胞特异性表达，可预防自身免疫性和链脲佐菌素诱导的糖尿病。”

Shen G-Q: "Asp905Tyr polymorphism of skeletal muscle-specific gycogen-targeting subunit of protein phosphatase 1 gene in non-insulin-dependent diabetes mellitus." Diabetes Care. 21. 1086-1089 (1998)

Shen G-Q：“非胰岛素依赖型糖尿病中蛋白磷酸酶 1 基因骨骼肌特异性糖原靶向亚基的 Asp905Tyr 多态性。”

Kawaguchi,Y: "Insulin gene region contributes to genetic susceptibility to,but may not to low incidence of,insulin dependent diabetes mellitus in Japanese" Biochemical and Biophysical Research Communication. 233. 283-287 (1997)

Kawaguchi,Y：“胰岛素基因区域有助于日本人胰岛素依赖型糖尿病的遗传易感性，但可能不会降低其发病率”《生物化学和生物物理研究通讯》。

Fujisawa T: "Meta-analysis of the association of Trp64Arg polymorphism of β3-adrenergic receptor gene with body mass index." J Clin Endocrinol Metab. 83. 2441-2444 (1998)

Fujisawa T：“β3-肾上腺素受体基因 Trp64Arg 多态性与体重指数关联的荟萃分析。”J Clin Endocrinol Metab 83. 2441-2444 (1998)