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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

基本信息

批准号：
8066816
负责人：
MICHELE M SALE
金额：
$ 14.35万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066816
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 Waist-Hip Ratio 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

项目摘要

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（由主要研究者提供）：估计有320万年龄在20岁或以上的非裔美国人患有T2 DM。这大约占AA人口的13%，并且在据信患有糖尿病的2000多万美国人中占很大比例，糖尿病是一种疾病，每年在直接和间接成本上花费美国超过1740亿美元。根据目前的趋势，2000年出生的AA中有40- 49%将在其一生中发展为T2 DM。已确定的糖尿病风险因素，如饮食和生活方式，在人群水平上定义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）已经成功地确定了影响欧洲人群糖尿病风险的遗传变异，但大多数对非洲裔人群的糖尿病风险没有重大影响。来自沿海南卡罗来纳州和格鲁吉亚海岛的非裔美国人患2型糖尿病的比率很高，混合水平很低，而且一般来说，饮食中富含饱和脂肪。我们推测，这种独特的祖先和环境因素的组合导致了糖尿病风险等位基因的更一致的突变，以及非洲起源的风险等位基因的富集。来自海岛家庭项目的现有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遗传研究的独特资源。我们的中心假设是，与EA相比，AA中T2 DM的风险增加部分是由于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进行鉴定。具体目标是：1）利用来自海岛家庭项目的DNA样本和数据识别2型糖尿病的遗传风险因素（1，236例，1，000例对照）和GWAS方法; 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，在独立的非洲裔美国人群体中进行糖尿病相关遗传变异的复制分析，通过基因分型来自卒中地理和种族差异原因（REGARDS）研究的受试者中最相关的变异（1%），从SC、GA和NC招募（1000例病例，1000例对照）; 3）使用脂蛋白亚类谱鉴定非裔美国人中脂蛋白亚类的遗传贡献者（VLDL、LDL和HDL的多个亚类的粒度和浓度），来自Aim 1的GWAS数据，并通过基因分型REGARDS受试者进行复制; 4）进一步探索与感兴趣的基因和区域中的后续研究的复制关联，所述后续研究可以包括（但不限于）相关变体的生物信息学评估、相关区域中增加的SNP密度、基因重测序和功能评估。该项目的基本原理是，识别和验证新的病理生理学途径以及明智地选择糖尿病风险的候选基因，将为在这一服务不足的高风险人群中开发新的、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。除了人类成本，2007年美国糖尿病的直接和间接成本超过17亿美元。非裔美国人患2型糖尿病的可能性是欧洲人的两倍。糖尿病影响超过320万非洲裔美国人，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。根据目前的趋势，2000年出生的AA中有40- 49%将在其一生中发展为T2 DM。已确定的糖尿病风险因素，如饮食和生活方式，在人群水平上定义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。识别使个体处于2型糖尿病风险中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经成功地确定了影响欧洲人群糖尿病风险的遗传因素，但大多数遗传因素对非洲裔人群的糖尿病风险没有重大影响。来自沿海的南卡罗来纳州和格鲁吉亚海岛的非裔美国人有很高的2型糖尿病发病率，现有的海岛家庭项目是确定糖尿病遗传因素的独特资源。我们建议应用这种经过验证的策略来确定新的治疗靶点，并将其转化为2型糖尿病的新诊断、预防和治疗策略。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-Biological (Fictive Kin and Othermothers): Embracing the Need for a Culturally Appropriate Pedigree Nomenclature in African-American Families.

非生物（虚构的亲属和其他母亲）：接受非裔美国家庭对文化上适当的谱系命名法的需要。

DOI：
发表时间：
2014
期刊：
Journal of National Black Nurses' Association : JNBNA
影响因子：
0
作者：
Spruill,IdaJ;Coleman,BerniceL;Powell-Young,YolandaM;Williams,TiffanyH;Magwood,Gayenell
通讯作者：
Magwood,Gayenell

African Americans' Culturally Specific Approaches to the Management of Diabetes.

非裔美国人治疗糖尿病的文化特定方法。