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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 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 万人受到糖尿病的影响 90-95% 的病例为 2 型。有许多与糖尿病相关的并发症，包括显着的糖尿病并发症心脏病和中风、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。有几个危险因素会导致个体对这种疾病发展的影响，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发展为 2 型糖尿病的风险。重要的少数群体中存在糖尿病健康差异，包括西班牙裔和非裔美国人，其中糖尿病患病率增加。流行病学和脂质组学研究的证据表明，特定脂蛋白及其组成脂质是2型糖尿病发生的重要因素，与许多其他代谢疾病一样，脂质代谢受到干扰。最经典的脂质参数通常与疾病风险相关的检查本身就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种类代表了更接近于表型和疾病之间相互作用的基因组水平，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 型糖尿病相关的基因的步伐。在这个项目中，我们将利用强大的扩展谱系中的全基因组序列（WGS）信息墨西哥裔美国人结合人类脂质组的综合测量，以确定影响脂质变异和 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的糖尿病健康差异很明显。这些精准的生物脂质组合表型和全基因组测序为我们提供了前所未有的机会来识别新基因和功能变异影响人体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 多种脂质种类的靶向脂质分析；以及多种代谢指标发挥作用并进行定量遗传分析； (II) 鉴定影响脂质变异的序列变异和使用全基因组测序（WGS）的所有个体都患有糖尿病；（Ill）在一个独立的墨西哥进行基于假设的复制美国人口； (IV) 对相关 iPSC 衍生的感兴趣变体进行功能评估细胞并分析该群体的一个子集中的游离脂肪酸和总脂肪酸含量。据估计，仅美国每年因糖尿病造成的经济负担就约为 2,450 亿美元，使这种疾病具有重大的公共卫生重要性。识别因果关系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参与疾病的生物途径疾病病理学。更好地了解遗传对血脂变异和糖尿病发展的贡献将为这种昂贵疾病的表征、治疗和潜在预防提供新方法。