Genetic contributors to diabetes and dyslipidemia in African Americans

描述(由首席研究员提供)：据估计，20岁或20岁以上的非洲裔美国人中有320万人患有T2 DM。这代表了大约13%的AA人口，以及据信患有糖尿病的2000多万美国人的相当大比例。糖尿病每年给美国造成超过1740亿美元的直接和间接成本。根据目前的趋势，2000年出生的再生障碍性贫血中，有40%-49%的人会在一生中患上2型糖尿病。已确立的糖尿病风险因素，如饮食和生活方式，在确定人群水平的糖尿病风险方面发挥了主要作用，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)已经成功地确定了在欧洲人群中影响糖尿病风险的基因变异，但大多数都不会对非洲裔人群的糖尿病风险产生重大影响。来自南卡罗来纳州和佐治亚州沿海海岛的非洲裔美国人患2型糖尿病的几率很高，混合饮料的水平很低，而且总体来说，他们的饮食中含有丰富的饱和脂肪。我们推测，祖先和环境因素的这种独特组合导致了糖尿病风险等位基因更一致的外显性，以及非洲起源的风险等位基因的丰富。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研究2型糖尿病和相关代谢特征(如血脂异常)的独特资源。我们的中心假设是，与EA相比，AA患者患T2 DM的风险增加，部分原因是非洲起源的易感等位基因，这些等位基因可以使用GWA进行识别。其具体目标是：1)利用来自海岛家庭项目(1,236例，1,000例对照)的DNA样本和数据和GWAS方法，识别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数据的荟萃分析，并通过对中风原因(关于)研究对象中最相关的10,000(1%)个变异进行基因分型，对独立的非裔美国人群体中与糖尿病相关的遗传变异进行复制分析；3)使用LipoScience，Inc.的核磁共振评估的脂蛋白亚类分布(VLDL、LDL和HDL的多个亚类的颗粒大小和浓度)、来自AIM 1的GWAS数据来识别非裔美国人脂蛋白亚类的遗传贡献者，并通过对受试者进行基因分型来进行复制；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，这些研究可能包括(但不限于)对相关变异的生物信息学评估、相关区域中增加SNP密度、基因重测序和功能评估。这个项目的基本原理是，识别和验证新的病理生理途径，并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危人群中开发新的、有针对性的预防和治疗策略提供信息。与公共健康相关：2型糖尿病占所有糖尿病的90%-95%，是美国和世界范围内最重要的公共健康问题之一。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。糖尿病影响着320多万非裔美国人，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。根据目前的趋势，2000年出生的再生障碍性贫血中，有40%-49%的人会在一生中患上2型糖尿病。已确立的糖尿病风险因素，如饮食和生活方式，在确定人群水平的糖尿病风险方面发挥了主要作用，但对个人风险的预测仍未实现。确定将个体置于2型糖尿病风险中的因素是制定治疗和预防策略的核心。最近的遗传学研究成功地确定了影响欧洲人群糖尿病风险的遗传因素，但大多数研究对非洲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海岛的非洲裔美国人患2型糖尿病的比率很高，现有的海岛家庭项目是确定糖尿病遗传因素的独特资源。我们建议应用这一经过验证的策略来确定新的治疗靶点，并允许将其转化为2型糖尿病的新诊断、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.