Biochemical and Genetic Markers of Type 2 Diabetes Risk

2 型糖尿病风险的生化和遗传标记

• 批准号: 7564098
• 负责人: Frank B Hu
• 金额: $ 52.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2010-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564098
• 关键词: Adipocytes; Adipose tissue; Affect; Age; American; Archives; Biochemical Genetics; Biological Markers; Blood specimen; Body fat; CD36 gene; Candidate Disease Gene; Central obesity; Code; Cohort Studies; Databases; Development; Diabetes Mellitus; Diet; Dietary Factors; Dietary intake; Disease; Documentation; E-Selectin; Esterified Fatty Acids; Evaluation; FABP4 gene; Fasting; Female; Funding; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genotype; Grant; Haplotypes; Hemoglobin; Hormones; IL6 gene; Individual; Inflammation; Insulin; Intercellular adhesion molecule 1; Interleukin-6; Leptin; Life Style; Link; Measures; Mediating; Metabolic Pathway; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nucleic Acid Regulatory Sequences; Nurses; Nurses' Health Study; Obesity; PPAR gamma; Pathogenesis; Pathway interactions; Peptides; Peroxisome Proliferator-Activated Receptors; Physical activity; Plasma; Polyunsaturated Fatty Acids; Prevention strategy; Principal Investigator; Production; Proinsulin; Public Health; RNA Splicing; Receptor Gene; Research Design; Resources; Risk; Risk Factors; Role; Site; Variant; Vascular Cell Adhesion Molecule-1; Woman; Work; adipokines; adiponectin; aged; case control; cohort; complement C3a, des-Arg-(77); cost; cytokine; design; diabetes risk; diet and exercise; fatty acid metabolism; fatty acid-binding proteins; follow-up; gene environment interaction; genetic variant; human FABP4 protein; indexing; intestinal fatty acid binding protein; leptin receptor; lifestyle factors; modifiable risk; novel; programs; prospective; receptor; resistin; waist circumference

DESCRIPTION (provided by applicant): This renewal application seeks to extend our prospective evaluation of predictors of type 2 diabetes mellitus (DM) in the Nurses' Health Study, a large prospective cohort with archived blood specimens. Type 2 DM is a major and increasing public health problem, affecting at least 17 million Americans. Obesity is strongly associated with risk for type 2 DM, yet mechanisms whereby obesity causes type 2 DM are uncertain. Recent evidence implicates "adipokines", including leptin and its receptors, acylation-stimulating protein (ASP), resistin, and adiponectin, and free fatty acids (FFA), all secreted by adipose tissue, in the pathogenesis of type 2 DM. We propose to study 1) the role of plasma levels of these adipokines and FFA as predictors of incident Type 2 DM, and 2) the association of specific genetic variants important in regulating adipokine and FFA metabolic pathways, including leptin receptor, resistin, IL-6, fatty acid binding proteins 2 and 4 (FABP2, FABP4), CD36, and peroxisome proliferators-activated receptor gamma coactivator- 1 (PGC 1), with risk of type 2 DM. Genetic studies will target putative functional variants in gene coding regions, and will also investigate associations between ancestral haplotypes at each locus and type 2 DM risk. We will also examine specific gene-environment interactions (including the role of diet, exercise, and obesity itself) and risk of type 2 DM. Elucidation of interrelationships among adipokines, FFA, their genetic determinants, lifestyle risk factors, and development of type 2 DM may suggest new treatment and/or prevention strategies. Previous work in this cohort has contributed to clarifying the major roles of body fat and its distribution, physical activity level, dietary factors, and inflammation as determinants of type 2 DM. We seek to build on this body of work by conducting nested case-control analyses in an existing database that includes 121,700 U.S. female nurses aged 35-55 at baseline, with follow-up and documentation through 2004 of 1,275 incident cases of type 2 DM among the 32,825 women who provided a blood sample in 1989-90. The unique features of this established cohort study, including its prospective design, large size, long duration, high follow-up rates (exceeding 90 percent over 28 years), availability of stored blood specimens, and cost-efficiency, make this database an unparalleled resource in the etiologic study of type 2 DM in women.

描述（由申请人提供）：本更新申请旨在扩展我们在护士健康研究中对2型糖尿病（DM）预测因子的前瞻性评估，这是一项包含存档血液标本的大型前瞻性队列研究。2型糖尿病是一个主要且日益严重的公共健康问题，影响着至少1700万美国人。肥胖与2型糖尿病的风险密切相关，但肥胖导致2型糖尿病的机制尚不确定。最近的证据表明，“脂肪因子”，包括瘦素及其受体、酰化刺激蛋白（ASP）、抵抗素、脂联素和游离脂肪酸（FFA），都是由脂肪组织分泌的，在2型发病机制中起作用