Genetic contributors to diabetes and dyslipidemia in African Americans

描述（由主要研究者提供）：估计有320万20岁或以上的非裔美国人患有2型糖尿病。这代表了大约13%的AA人口和2000多万美国人被认为患有糖尿病的很大一部分，这种疾病每年花费美国超过1740亿美元的直接和间接费用。按照目前的趋势，2000年出生的AA中有40- 49%的人会在一生中患上2型糖尿病。既定的糖尿病风险因素，如饮食和生活方式，在确定人群水平的糖尿病风险方面起着重要作用，但对个人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，但大多数对非洲人后裔的糖尿病风险没有重大影响。来自南卡罗来纳沿海岛屿和乔治亚州的非裔美国人患2型糖尿病的比例高，混合饮食水平低，通常饮食中含有丰富的饱和脂肪。我们假设，这种独特的祖先和环境因素的结合导致了糖尿病风险等位基因的更一致的外显率，以及非洲血统风险等位基因的丰富。来自海岛家族项目的现有DNA样本和丰富的表型数据为2型糖尿病和相关代谢特征（如血脂异常）的遗传研究提供了独特的资源。我们的中心假设是，AA与EA相比，患2型糖尿病的风险增加部分是由于非洲血统的易感等位基因，这些等位基因可以通过GWAS识别。具体目标是：1)利用DNA样本和来自海岛家庭项目（1236例，1000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)利用与杰克逊心脏研究和维克森林大学研究合作的GWAS数据的荟荟性分析，对独立的非洲裔美国人人群中糖尿病相关的遗传变异进行复制分析，并通过对来自中风地理和种族差异原因（REGARDS）研究的受试者中多达10,000（1%）最相关的变异进行基因分型，这些受试者来自SC， GA和NC（1000例，1000例对照）；3)利用LipoScience， Inc.的核磁共振评估的脂蛋白亚类谱（VLDL、LDL和HDL多个亚类的颗粒大小和浓度），以及Aim 1的GWAS数据，确定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)通过对感兴趣的基因和区域的后续研究，进一步探索可复制的关联，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鉴定和验证新的病理生理途径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提供新的、有针对性的预防和治疗策略。公共卫生相关性：2型糖尿病占所有糖尿病的90- 95%，是美国乃至全世界最重要的公共卫生问题之一。除了人力成本，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裔美国人的两倍。糖尿病影响了320多万非裔美国人，并导致了一系列毁灭性的并发症，包括心脏病发作、中风、肾衰竭、失明、截肢和神经痛。按照目前的趋势，2000年出生的AA中有40- 49%的人会在一生中患上2型糖尿病。既定的糖尿病风险因素，如饮食和生活方式，在确定人群水平的糖尿病风险方面起着重要作用，但对个人风险的预测仍未实现。确定个体患2型糖尿病风险的因素是制定治疗和预防策略的核心。最近的遗传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人后裔的糖尿病风险没有重大影响。来自南卡罗来纳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确定糖尿病遗传因素的独特资源。我们建议应用这一已证实的策略来确定新的治疗靶点，并允许转化为新的2型糖尿病的诊断、预防和治疗策略。

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.