Assessing the Influence of the Human Lipidome on Risk of Diabetes in a Minority Population

项目总结 2型糖尿病是一个主要的公共卫生问题。目前仅在美国就有2580万人患上糖尿病 90%-95%的病例是2型。糖尿病有许多相关的并发症，包括显著的 心脏病和中风、失明、肾功能衰竭和肾脏疾病、非酒精性脂肪肝的风险增加 疾病、神经病、听力损失和下肢截肢。有几个风险因素会导致 包括性别、年龄和种族等人口学特征在内的个人与该病的发展有关； 以及与行为和生活方式相关的改变。此外，代谢决定因素，如血糖受损 耐受性和胰岛素抵抗会增加个体进展为2型糖尿病的风险。意义重大 糖尿病健康差距存在于少数群体中，包括西班牙裔和非裔美国人，他们 糖尿病的患病率正在增加。流行病学和脂质学研究的证据表明， 特异脂蛋白及其组成脂是2型糖尿病发生发展的重要因素， 与许多其他代谢性疾病一样，脂肪代谢也会受到干扰。最经典的血脂参数 通常与疾病风险相关的检查是由多种脂质组成的复杂实体本身 物种。我们假设这些基本脂质物种代表的中间表型更接近于 基因组水平在表型和疾病之间的相互作用中，因此可能是更好的疾病预测因子 风险和加快发现与血脂变化和2型糖尿病有关的基因的速度。 在这个项目中，我们将利用强大的扩展家系中的全基因组序列(WGS)信息 墨西哥裔美国人结合人类脂体的全面测量，来识别 影响血脂变化和2型糖尿病的新基因和功能变异，以努力减少 西班牙裔人群中存在明显的糖尿病健康差距。这些精确的生物脂结合在一起 表型和WGS给了我们一个前所未有的机会来鉴定新的基因和功能变异 影响人类血脂变化和糖尿病风险。为了实现这些目标，我们将(I)衡量T2D风险 表型包括800多种脂类的靶向脂谱；以及多种新陈代谢指标 功能，并进行定量遗传分析；(Ii)识别影响血脂变异的序列变异和 使用WGS的所有个体中的糖尿病；(Ill)在独立的墨西哥人中执行基于假设的复制 美国人口；和(4)对相关IPSC衍生的感兴趣的变体进行功能评估 细胞，并分析队列子集中的游离和总脂肪酸含量。 据估计，仅在美国，糖尿病每年造成的经济负担约为2450亿美元， 使这种疾病对公共卫生具有重大意义。识别与疾病因果相关的基因的能力 疾病风险提供了一个无与伦比的机会来快速确定涉及到 疾病病理学。更好地了解遗传因素对血脂变化和糖尿病发生的影响 将为这种代价高昂的疾病的特征、治疗和潜在预防提供新的方法。

PROJECT SUMMARY Type 2 diabetes is a major public health concern. Diabetes currently affects 25.8 million people in the US alone and 90-95% of all cases are type 2. There are many complications related to diabetes, including a significantly increased risk of heart disease and stroke, blindness, kidney failure and kidney disease, nonalcoholic fatty liver disease, neuropathy, hearing loss and lower-limb amputations. There are several risk factors predisposing individuals to the development of this disease including demographic characteristics like sex, age and ethnicity; and behavioral and lifestyle-related modifications. In addition, metabolic determinants such as impaired glucose tolerance and insulin resistance increase the risk of an individual progressing to type 2 diabetes. Significant diabetes health disparities exist in minority populations, including Hispanics and African Americans, where prevalence of diabetes is increased. Evidence from both epidemiological and lipidomic studies have shown that specific lipoproteins and their constituent lipids are important factors in the development of type 2 diabetes, where, like many other metabolic diseases, lipid metabolism is disrupted. The classical lipid parameters most commonly examined in relation to disease risk are themselves complex entities composed of multiple lipid species. We hypothesize that these basic lipid species represent intermediate phenotypes that lie closer to the genomic level in the interplay between phenotype and disease, and therefore may be better predictors of disease risk and increase the pace of discovery of genes causally involved in lipid variation and type 2 diabetes. In this project, we will exploit whole genome sequence (WGS) information in powerful extended pedigrees of Mexican American individuals in combination with comprehensive measures of the human lipidome, to identify novel genes and functional variants influencing lipid variation and type 2 diabetes, in an effort to reduce the diabetes health disparities evident in Hispanic populations. The combination of these precise biological lipid phenotypes and WGS gives us an unprecedented opportunity to identify novel genes and functional variants influencing human lipid variation and risk of diabetes. To achieve these objectives, we will (I) measure T2D risk phenotypes including targeted lipid profiling of more than 800 lipid species; and multiple measures of metabolic function, and perform quantitative genetic analyses; (II) identify sequence variation influencing lipid variation and diabetes in all individuals using WGS; (Ill) perform hypothesis based replication in an independent Mexican American population; and (IV) perform functional assessments of variants of interest in relevant iPSC-derived cells and analyze free and total fatty acid content in a subset of the cohort. The estimated economic burden of diabetes in the United States alone is approximately $245 billion per year, making this disease of major public health importance. The ability to identify genes that are causally involved in disease risk provides an unparalleled opportunity to quickly determine biological pathways that are involved in disease pathology. A better understanding of the genetic contribution to lipid variation and diabetes development will provide novel approaches for the characterization, treatment and potential prevention of this costly disease.