Genetic modifiers of diabetes in cystic fibrosis

囊性纤维化中糖尿病的遗传修饰

• 批准号: 7641336
• 负责人: SCOTT M BLACKMAN
• 金额: $ 17.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641336
• 关键词: 20 year old; Adolescence; Affect; Age; Alleles; Caring; Child; Clinical; Complication; Cystic Fibrosis; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Early identification; Environmental Risk Factor; Exocrine pancreas; Family; Family history of; Fasting; Functional disorder; General Population; Genes; Genetic; Genetic Variation; Genome; Genotype; Glucose; Goals; Hereditary Disease; Individual; Insulin; Joints; Light; Methods; Minnesota; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; OGTT; Parents; Patients; Phenotype; Play; Population; Predisposition; Principal Investigator; Quality Control; Recruitment Activity; Research Design; Risk; Risk Factors; Role; Screening procedure; Siblings; Single Nucleotide Polymorphism; Steroids; Susceptibility Gene; TCF7L2 gene; Test Result; Testing; Twin Multiple Birth; Variant; base; body system; case control; cystic fibrosis patients; density; diabetes risk; diabetic; genetic profiling; genetic variant; genome wide association study; high risk; improved; insight; meetings; mortality; non-genetic; novel diagnostics; programs; public health relevance; pulmonary function; transmission process; 20 year old; Adolescence; Affect; Age; Alleles; Caring; Child; Clinical; Complication; Cystic Fibrosis; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Early identification; Environmental Risk Factor; Exocrine pancreas; Family; Family history of; Fasting; Functional disorder; General Population; Genes; Genetic; Genetic Variation; Genome; Genotype; Glucose; Goals; Hereditary Disease; Individual; Insulin; Joints; Light; Methods; Minnesota; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; OGTT; Parents; Patients; Phenotype; Play; Population; Predisposition; Principal Investigator; Quality Control; Recruitment Activity; Research Design; Risk; Risk Factors; Role; Screening procedure; Siblings; Single Nucleotide Polymorphism; Steroids; Susceptibility Gene; TCF7L2 gene; Test Result; Testing; Twin Multiple Birth; Variant; base; body system; case control; cystic fibrosis patients; density; diabetes risk; diabetic; genetic profiling; genetic variant; genome wide association study; high risk; improved; insight; meetings; mortality; non-genetic; novel diagnostics; programs; public health relevance; pulmonary function; transmission process

DESCRIPTION (provided by applicant): Genome-wide association studies have identified at least 9 genetic loci whose variation influences risk for type 2 diabetes. The mechanisms by which they cause disease remain to be elucidated. However, diabetes occurring as a complication of other diseases may involve some of the same mechanisms as type 2 diabetes, allowing studies of one disease to inform the other. Cystic fibrosis (CF) is a genetic disease involving the exocrine pancreas in which patients develop diabetes at a high rate as they reach adolescence and young adulthood. Using data from the U.S. CF Twin and Sibling study, we have shown that genetic modifiers (other than the gene that causes CF) are the primary cause of diabetes in CF. Also, we showed that CF patients with a family history of type 2 diabetes have a three-fold greater risk of developing diabetes themselves. These findings indicate that the same genes may affect diabetes susceptibility in both CF patients and in the general population. Indeed, we have shown that a susceptibility gene for type 2 diabetes, TCF7L2, is associated with increased risk for diabetes in CF in two independent study groups. Thus, diabetes susceptibility genes of low effect in the general population may play a key role in this important complication of CF. The overall goals of this proposal are to identify genetic modifiers for diabetes in CF, assess their role in type 2 diabetes, and delineate important factors influencing their impact on disease. These goals will be met by performing a high-density genome-wide scan for association with diabetes in C Fin a large group of recruited CF patients and families. Variants associated with diabetes in CF will be tested in already characterized type 2 diabetes study groups, and previously identified type 2 diabetes variants will be tested in CF patients. Finally, we will identify the impact of clinical and environmental factors on the effect of TCF7L2 and other identified variants, using study groups recruited specifically for high-quality diabetes-related information such as BM1, steroid use, and oral glucose tolerance test results. This information will allow early identification of CF patients at high risk for diabetes, will allow testing of therapies with regards to underlying genetic profile, and will improve our understanding of diabetes not only for CF patients but for diabetes in the general population. PUBLIC HEALTH RELEVANCE: Characterization of modifier genes for diabetes in CF will improve targeting and individualization of diabetes screening and therapy for CF patients, will allow tests of new therapies to be interpreted in light of a patient's underlying genetic profile, and will improve our understanding of diabetes not only for CF patients but for diabetes in the general population.

描述（由申请人提供）： 全基因组关联研究已经确定了至少9个遗传基因座，其变异会影响2型糖尿病的风险。它们引起疾病的机制依然阐明。但是，作为其他疾病并发症发生的糖尿病可能涉及与2型糖尿病相同的机制，从而使一种疾病的研究能够告知另一种疾病。囊性纤维化（CF）是一种遗传疾病，涉及外分泌胰腺，其中患者在青春期和成年后以高率患糖尿病。使用来自美国CF双胞胎和兄弟姐妹研究的数据，我们表明遗传修饰剂（导致CF的基因除外）是CF中糖尿病的主要原因。另外，我们表明患有2型糖尿病家族史的CF患者患糖尿病的风险大三倍。这些发现表明，相同的基因可能会影响CF患者和普通人群的糖尿病敏感性。实际上，我们已经表明，针对2型糖尿病TCF7L2的易感基因与两个独立研究组中CF的糖尿病风险增加有关。因此，在普通人群中，糖尿病的易感性基因在CF的这一重要并发症中可能起关键作用。该提案的总体目标是确定CF中糖尿病的遗传修饰剂，评估其在2型糖尿病中的作用，并描述影响其对疾病影响的重要因素。这些目标将通过进行高密度的全基因组扫描来实现，以与C FIN中的一大群招募的CF患者和家庭相关。与CF中与糖尿病相关的变异将在已经表征的2型糖尿病研究组中进行测试，并且先前鉴定的2型糖尿病变体将在CF患者中测试。最后，我们将使用专门针对高质量糖尿病相关的信息（例如BM1，类固醇使用和口服糖耐受性测试结果）招募的研究组来确定临床和环境因素对TCF7L2和其他确定变体的影响的影响。该信息将允许早期鉴定患有糖尿病高风险的CF患者，将允许对基本遗传特征的疗法进行测试，并将提高我们对CF患者的糖尿病的理解，不仅对CF患者，而且对普通人群中的糖尿病。 公共卫生相关性：CF中糖尿病的修饰基因的特征将改善CF患者糖尿病筛查和疗法的靶向和个性化，将允许根据患者的基本遗传学特征来解释新疗法的测试，并将不仅对CF患者的糖尿病的理解，而且对CF患者的理解也可以改善我们对CF患者的理解。