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

评估人类脂质组对少数人群糖尿病风险的影响

• 批准号: 10671833
• 负责人: JOANNE E. CURRAN
• 金额: $ 20.45万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671833
• 关键词: Affect; African American population; Age; Apolipoproteins B; Behavioral; Biological; Blindness; C-Peptide; Cells; Characteristics; Cholesterol; Chromosome Mapping; Complex; Cost of Illness; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Disease; Disease susceptibility; Drug Targeting; Economic Burden; Epidemic; Epidemiology; Ethnic Origin; Family Study; Fatty Acids; Genes; Genetic; Genetic Markers; Genetic Variation; Genomics; Genotype; Heritability; High Density Lipoproteins; Hispanic Americans; Hispanic Populations; Human; Impairment; Individual; Insulin; Insulin Resistance; Kidney Diseases; Kidney Failure; Lead; Life Style; Lipids; Lipoproteins; Low-Density Lipoproteins; Lower Extremity; Measures; Metabolic; Metabolic Diseases; Metabolic syndrome; Methods; Mexican Americans; Minority Groups; Modification; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Pathway interactions; Persons; Phenotype; Phospholipids; Plasma; Population; Populations at Risk; Predisposing Factor; Predisposition; Prevalence; Prevention; Proinsulin; Proteins; Public Health; Quantitative Genetics; Quantitative Trait Loci; Risk; Risk Factors; Sampling; Sequence Analysis; Stroke; Testing; Tissues; Triglycerides; United States; Variant; Visit; base; causal variant; cohort; design; diabetes risk; disease phenotype; disorder risk; endophenotype; epidemiology study; ethnic minority population; fasting glucose; gene discovery; genetic analysis; genetic pedigree; genetic variant; genome sequencing; health disparity; hearing impairment; heart disease risk; impaired glucose tolerance; induced pluripotent stem cell; insulin secretion; interest; limb amputation; lipid metabolism; lipidome; lipidomics; non-alcoholic fatty liver disease; novel; novel strategies; particle; sex; success; trait; validation studies; whole genome

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.

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会影响2580万人 所有情况中有90-95％是2型。与糖尿病有关的并发症很多，包括明显 心脏病和中风，失明，肾衰竭和肾脏疾病的风险增加 疾病，神经病，听力丧失和下限截肢。有几个危险因素 个人发展这种疾病，包括性别，年龄和种族等人口特征； 以及与行为和生活方式相关的修改。另外，代谢决定因素（例如葡萄糖受损） 耐受性和胰岛素抵抗会增加个人发展为2型糖尿病的风险。重要的 糖尿病的健康差异存在于少数群体中，包括西班牙裔和非裔美国人，那里 糖尿病患病率增加。流行病学和脂肪组学研究的证据表明 特定的脂蛋白及其成分脂质是2型糖尿病发展的重要因素， 像许多其他代谢疾病一样，脂质代谢也受到干扰。经典脂质参数最多 通常与疾病风险有关的通常是由多种脂质组成的复杂实体 物种。我们假设这些基本脂质物种代表了更接近靠近的中间表型 表型与疾病之间相互作用的基因组水平，因此可能是疾病的更好预测指标 风险并增加与脂质变异和2型糖尿病有关的基因发现的速度。 在这个项目中，我们将利用强大的扩展血统书来利用整个基因组序列（WGS）信息 墨西哥裔美国人与人类脂肪组的全面措施结合使用，以识别 影响脂质变异和2型糖尿病的新型基因和功能变体，以减少 西班牙裔人群中明显的糖尿病健康差异。这些精确的生物脂质的结合 表型和WGS为我们提供了识别新基因和功能变体的前所未有的机会 影响人类脂质变异和糖尿病风险。为了实现这些目标，我们将（i）衡量T2D风险 表型，包括800多种脂质物种的靶向脂质分析；和代谢的多种措施 功能，并执行定量遗传分析； （ii）确定影响脂质变化和的序列变化 所有使用WGS的人的糖尿病； （生病）在独立墨西哥人中进行基于假设的复制 美国人口； （iv）对IPSC衍生的相关IPSC中感兴趣的变体进行功能评估 细胞并分析队列子集中的自由和总脂肪酸含量。 仅在美国，估计的糖尿病经济负担每年约为2450亿美元， 使这种具有重大公共健康的疾病重要。识别因果关系涉及的基因的能力 疾病风险提供了一个无与伦比的机会，可以快速确定涉及的生物途径 疾病病理学。更好地了解对脂质变异和糖尿病发育的遗传贡献 将提供新颖的方法来表征，治疗和潜在预防这种昂贵的疾病。