Genetic contributors to diabetes and dyslipidemia in African Americans

非裔美国人糖尿病和血脂异常的遗传因素

• 批准号: 7698255
• 负责人: MICHELE M SALE
• 金额: $ 300.89万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7698255
• 关键词: 20 year old; 6H,8H-3,4-dihydropyrimido(4,5-c)(1,2)oxazin-7-one; Accounting; Address; Admixture; Affect; Africa; African; African American; Age; Albumins; Alleles; American; Amputation; Ancillary Study; Bioinformatics; Biological; Blindness; Blood Pressure; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Collaborations; Computer Simulation; Cost of Illness; Country; Creatinine; DNA; DNA Resequencing; Data; Development; Diabetes Mellitus; Diastolic blood pressure; Diet; Direct Costs; Dyslipidemias; Environmental Risk Factor; European; Evaluation; Facilities and Administrative Costs; Family; Follow-Up Studies; Genes; Genetic; Genetic Materials; Genetic Predisposition to Disease; Genome Scan; Genomics; Genotype; Glycosylated hemoglobin A; Goals; Heart; High Density Lipoprotein Cholesterol; Hip region structure; Human; Incidence; Individual; Investigation; Island; Kidney Failure; LDL Cholesterol Lipoproteins; Life; Life Style; Lipids; Lipoproteins; Low-Density Lipoproteins; Measures; Meta-Analysis; Metabolic; Metabolic syndrome; Methods; Mind; Myocardial Infarction; N.I.H. Research Support; National Human Genome Research Institute; Nerve Pain; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Obesity; Outcome; Particle Size; Pathway interactions; Patients; Penetrance; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Prevention strategy; Principal Investigator; Public Health; Pulse Pressure; Race; Reasons for Geographic And Racial Differences in Stroke; Recruitment Activity; Registries; Renal function; Research; Research Design; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; SNP genotyping; Sampling; Scanning; Sea; Serum; South Carolina; Stroke; Testing; Translations; Triglycerides; Universities; Validation; Variant; Very low density lipoprotein; base; clinical phenotype; density; diabetes risk; diabetic; experience; fasting glucose; follow-up; forest; genetic resource; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; improved; innovation; interest; new therapeutic target; non-diabetic; novel; novel diagnostics; painful neuropathy; pressure; prevent; public health relevance; saturated fat; sex; sugar; therapeutic development; trait; treatment strategy; trend; urinary; waist circumference

DESCRIPTION (provided by principal investigator): It is estimated that 3.2 million African Americans aged 20 years or older have T2DM. This represents approximately 13 percent of the AA population and a significant proportion of the more than 20 million Americans believed to be living with diabetes, a disease that costs the U.S. over $174 billion a year in direct and indirect costs. Given current trends, 40-49 percent of AA born in 2000 will develop T2DM in their lifetime. Established diabetes risk factors such as diet and lifestyle play major roles in defining diabetes risk at a population level, but prediction of individual risk remains unrealized. Recent genome-wide association studies (GWAS) have successfully identified genetic variants that influence diabetes risk in European populations, however most do not have a major impact on diabetes risk in populations of African descent. The African American population from the Sea Islands of coastal South Carolina and Georgia has high rates of type 2 diabetes, low levels of admixture and, in general, consumes a diet rich in saturated fats. We postulate that this unique combination of ancestral and environmental factors results in a more consistent penetrance of diabetes risk alleles, as well as enrichment of risk alleles of African origin. The existing DNA samples and rich phenotypic data from the Sea Island Families Project comprise a unique resource for genetic studies of type 2 diabetes and related metabolic traits such as dyslipidemia. Our central hypothesis is that the increased risk for T2DM in AA compared with EA is due, in part, to susceptibility alleles of African origin, and that these alleles can be identified using a GWAS. The Specific Aims are to: 1) Identify genetic risk factors for type 2 diabetes utilizing DNA samples and data from the Sea Island Families Project (1,236 cases, 1,000 controls) and a GWAS approach; 2) Conduct replication analyses of diabetes-associated genetic variants in independent African American populations using meta-analyses of GWAS data in collaboration with the Jackson Heart Study and Wake Forest University Study, and by genotyping up to 10,000 (1 percent) of the most-associated variants in subjects from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, recruited from SC, GA and NC (1,000 cases, 1000 controls); 3) Identify genetic contributors to lipoprotein subclasses in African Americans using the lipoprotein subclass profile (particle size and concentration for multiple subclasses of VLDL, LDL, and HDL) assessed by NMR at LipoScience, Inc., the GWAS data from Aim 1, and conduct replication by genotyping REGARDS subjects; 4) Further explore replicated associations with follow-up studies in genes and regions of interest that may include (but are not limited to) bioinformatic evaluation of associated variants, increasing SNP density in associated regions, gene resequencing, and functional evaluation. The rationale for this project is that identification and validation of novel pathophysiological pathways and informed selection of candidate genes for diabetes risk will inform development of new, targeted prevention and treatment strategies in this underserved, high risk population. PUBLIC HEALTH RELEVANCE: Type 2 diabetes accounts for 90-95 percent of all diabetes and constitutes one of the most important public health problems in the U.S. and worldwide. Beyond the human cost, the direct and indirect costs of diabetes in the U.S. exceeded $1.7 billion in 2007. African American individuals are twice as likely to have type 2 diabetes as European Americans. Diabetes affects over 3.2 million African Americans, and leads to a devastating range of complications, including heart attack, stroke, kidney failure, blindness, amputation, and nerve pain. Given current trends, 40-49 percent of AA born in 2000 will develop T2DM in their lifetime. Established diabetes risk factors such as diet and lifestyle play major roles in defining diabetes risk at a population level, but prediction of individual risk remains unrealized. Identification of factors that place individuals at risk for type 2 diabetes is central to the development of therapeutic and preventive strategies. Recent genetic studies have successfully identified inherited factors that influence diabetes risk in European populations, however most do not have a major impact on diabetes risk in populations of African descent. The African American population from the Sea Islands of coastal South Carolina and Georgia has high rates of type 2 diabetes, and the existing Sea Island Families Project is a unique resource for identifying inherited factors for diabetes. We propose applying this proven strategy to identify new therapeutic targets and allow translation to novel diagnostic, prevention, and treatment strategies for type 2 diabetes.

描述（由首席研究员提供）：据估计，20 岁或以上的非裔美国人中有 320 万患有 T2DM。这约占 AA 人口的 13%，也是超过 2000 万美国人中被认为患有糖尿病的很大一部分，这种疾病每年给美国造成的直接和间接损失超过 1740 亿美元。鉴于目前的趋势，2000 年出生的 AA 中有 40-49% 在一生中会患上 T2DM。饮食和生活方式等已确定的糖尿病风险因素在确定人群水平的糖尿病风险方面发挥着重要作用，但对个体风险的预测仍未实现。最近的全基因组关联研究（GWAS）已成功识别出影响欧洲人群糖尿病风险的遗传变异，但大多数对非洲人后裔人群的糖尿病风险没有重大影响。来自南卡罗来纳州和佐治亚州沿海岛屿的非裔美国人患 2 型糖尿病的比例很高，混合水平较低，并且通常饮食富含饱和脂肪。我们假设祖先和环境因素的这种独特组合导致糖尿病风险等位基因的外显率更加一致，以及非洲起源的风险等位基因的富集。海岛家族项目现有的 DNA 样本和丰富的表型数据构成了 2 型糖尿病和血脂异常等相关代谢特征的遗传研究的独特资源。我们的中心假设是，与 EA 相比，AA 中 T2DM 风险增加的部分原因是非洲起源的易感性等位基因，并且这些等位基因可以使用 GWAS 进行识别。具体目标是： 1) 利用 DNA 样本和海岛家庭项目（1,236 例，1,000 例对照）的数据和 GWAS 方法确定 2 型糖尿病的遗传风险因素； 2) 与杰克逊心脏研究和维克森林大学研究合作，使用 GWAS 数据的荟萃分析，对独立非裔美国人中与糖尿病相关的遗传变异进行复制分析，并对来自南卡罗来纳州、乔治亚州和北卡罗来纳州招募的卒中地理和种族差异原因 (REGARDS) 研究对象中最多 10,000 个 (1%) 最相关的变异进行基因分型（1,000 个） 病例，1000 个对照）； 3) 使用 LipoScience, Inc. 的 NMR 评估的脂蛋白亚类概况（VLDL、LDL 和 HDL 多个亚类的粒径和浓度）、来自目标 1 的 GWAS 数据，识别非裔美国人脂蛋白亚类的遗传因素，并通过基因分型 REGARDS 受试者进行复制； 4) 进一步探索与基因和感兴趣区域的后续研究的重复关联，可能包括（但不限于）相关变异的生物信息学评估、增加相关区域的SNP密度、基因重测序和功能评估。该项目的基本原理是，新的病理生理学途径的识别和验证以及糖尿病风险候选基因的知情选择将为这一服务不足的高风险人群制定新的、有针对性的预防和治疗策略提供信息。公共卫生相关性：2 型糖尿病占所有糖尿病的 90-95%，是美国和全世界最重要的公共卫生问题之一。除了人力成本之外，2007 年美国糖尿病的直接和间接成本超过了 17 亿美元。非洲裔美国人患 2 型糖尿病的可能性是欧洲裔美国人的两倍。糖尿病影响超过 320 万非裔美国人，并导致一系列毁灭性的并发症，包括心脏病发作、中风、肾衰竭、失明、截肢和神经疼痛。鉴于目前的趋势，2000 年出生的 AA 中有 40-49% 在一生中会患上 T2DM。饮食和生活方式等已确定的糖尿病风险因素在确定人群水平的糖尿病风险方面发挥着重要作用，但对个体风险的预测仍未实现。识别导致个体面临 2 型糖尿病风险的因素对于制定治疗和预防策略至关重要。最近的遗传学研究已成功确定了影响欧洲人群糖尿病风险的遗传因素，但大多数对非洲人后裔人群的糖尿病风险没有重大影响。来自南卡罗来纳州和乔治亚州沿海海岛的非裔美国人患 2 型糖尿病的比例很高，现有的海岛家庭项目是识别糖尿病遗传因素的独特资源。我们建议应用这一经过验证的策略来确定新的治疗靶点，并转化为 2 型糖尿病的新诊断、预防和治疗策略。