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

项目摘要 2型糖尿病是一个主要的公共卫生问题。糖尿病目前仅在美国就影响着2580万人 90-95%的病例是2型。有许多与糖尿病有关的并发症，包括一个显著的 心脏病和中风、失明、肾衰竭和肾脏疾病、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。有几个风险因素诱发 个体与这种疾病的发展，包括人口统计学特征，如性别，年龄和种族; 以及行为和生活方式相关的改变。此外，代谢决定因素，如受损葡萄糖 耐受性和胰岛素抗性增加个体发展为2型糖尿病的风险。显著 糖尿病健康差异存在于少数群体，包括西班牙裔和非洲裔美国人， 糖尿病患病率增加。流行病学和脂质组学研究的证据表明， 特异性脂蛋白及其组成脂质是2型糖尿病发展的重要因素， 像许多其他代谢疾病一样，脂质代谢被破坏。经典的血脂参数 通常检查与疾病风险有关的是由多种脂质组成的复杂实体， 物种我们假设这些碱性脂质物质代表了更接近于 基因组水平在表型和疾病之间的相互作用，因此可能是更好的疾病预测因子 风险，并加快发现与血脂变异和2型糖尿病有关的基因的步伐。 在这个项目中，我们将利用全基因组序列（WGS）信息，在强大的扩展谱系， 结合墨西哥裔美国人个体的人体脂质体综合测定， 影响血脂变异和2型糖尿病的新基因和功能变体， 西班牙裔人群的糖尿病健康差异明显。这些精确的生物脂质 表型和WGS为我们提供了一个前所未有的机会，以确定新的基因和功能变体 影响人体脂质变化和糖尿病风险。为了实现这些目标，我们将（I）衡量T2 D风险 表型，包括800多种脂质的靶向脂质分析;以及多种代谢指标， 功能，并进行定量遗传分析;（II）确定影响脂质变异的序列变异， 在所有使用WGS的个体中进行基于假设的复制;（III）在独立的墨西哥人中进行基于假设的复制。 （IV）对相关iPSC衍生的细胞中感兴趣的变体进行功能评估。 细胞并分析组群的子集中的游离脂肪酸和总脂肪酸含量。 仅在美国，糖尿病的估计经济负担就约为每年2450亿美元， 使这种疾病成为重要的公共卫生问题。能够识别基因的因果关系参与， 疾病风险提供了一个无与伦比的机会，以快速确定生物途径，参与 疾病病理学更好地了解遗传因素对血脂变异和糖尿病发展的影响 将为这种昂贵疾病的表征、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.