Investigating the Genetic Basis of Metabolic Disease and Familial Dysceramidemia in Pacific Islanders

调查太平洋岛民代谢性疾病和家族性神经酰胺血症的遗传基础

• 批准号: 10286704
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286704
• 关键词: Affect; Anabolism; Apoptosis; Arterial Fatty Streak; Beta Cell; Biological Models; Biology; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Ceramidase; Ceramides; Code; Community Networks; Complex; Complications of Diabetes Mellitus; Computerized Medical Record; Data; Databases; Development; Diabetes Mellitus; Diagnostic; Disease; End stage renal failure; Enrollment; Enzymes; Family; Family member; Foundations; Functional disorder; Future; Genealogy; Generations; Genes; Genetic; Genetic Screening; Genetic Variation; Genomics; Goals; Health; Homeostasis; Human; Hypertension; Impairment; Individual; Insulin; Kidney Diseases; Kidney Failure; Lipids; Liquid Chromatography; Literature; Malignant Neoplasms; Metabolic Diseases; Metabolism; Mexican Americans; Modification; Mutation; Nonesterified Fatty Acids; Obesity; Pacific Island Americans; Pacific Islands; Pathway interactions; Pharmacology; Population Database; Recording of previous events; Research; Research Design; Research Project Grants; Resources; Risk; Role; Solid; Sphingolipids; Sphingosine; Testing; Therapeutic; Translations; Universities; Utah; Variant; base; cohort; comorbidity; diabetic patient; dihydroceramide; exome sequencing; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; human disease; improved; insight; lipidomics; member; multiple omics; mutation carrier; non-genetic; novel; population based; rare variant; recruit; sphinganine; tandem mass spectrometry

PROJECT SUMMARY Pacific Islanders (PIs) have among the world’s highest burden of metabolic disease and are at increased risk for other associated comorbidities, such as cardiovascular disease, kidney disease, and cancer. Despite high rates of these complex diseases, PIs have largely been underrepresented in studies designed to identify the underlying factors that contribute to their increased risk. Ceramides are lipotoxic sphingolipids that contribute to cellular dysfunction that cause metabolic disease. While much of the literature implicating ceramides in metabolic disease has centered on genetic modification or pharmacological inhibition of genes involved in ceramide synthesis pathways in various model systems, accumulation of ceramides has also been demonstrated in human disease. The underlying mechanisms leading to increased ceramides in human disease, however, are unknown. As part of our studies leveraging unique resources at the University of Utah, including the Utah Diabetes Database and the Utah Population Database, we recently identified rare mutations that alter ceramide levels in 2 families enriched for obesity, diabetes, and end-stage renal disease, causing familial dysceramidemia, including the first family from the Pacific Islands with a rare genetic variant associated with elevated ceramides. Given this novel and important finding, we hypothesize that aberrant sphingolipid levels and genetic variants that alter their biosynthesis are key contributors to metabolic disease and related comorbidities in PIs. Building on this evidence, the goal of this developmental research project is to expand this research and investigate the role of sphingolipid levels in metabolic disease in PIs using a multi-omics approach that includes lipidomic and genomic analysis of large, multi-generational PI pedigrees. To accomplish this goal, we will 1) determine sphingolipid levels in members of 25 large, multi-generational PI pedigrees with metabolic disease by i) expanding recruitment of PI families currently enrolled in the Utah Diabetes and Diabetic Complications Study to include at least 10-15 members per family and ii) use liquid chromatography with tandem mass spectrometry to establish lipid profiles of sphingolipid species in all recruited PI family members and 2) evaluate the contribution of genetic variation on sphingolipid levels in members of large, multi-generational PI pedigrees by i) screening for genetic variants in members of PI families with aberrant sphingolipid profiles using whole exome sequencing and ii) performing unified linkage analysis and rare variant association testing to identify variants influencing sphingolipid species. We anticipate that this research will build on exciting preliminary data and provide key insights on the role of this pathway in metabolic disease in PIs. This research will provide a solid foundation for future efforts aimed at elucidating the mechanisms behind the disparity of metabolic disease in PIs and facilitate translation of these findings to improved diagnostics and therapeutics.

项目总结 太平洋岛民(PI)是世界上代谢性疾病负担最重的国家之一，而且 其他相关合并症的风险，如心血管疾病、肾脏疾病和癌症。尽管 这些复杂疾病的高发病率，在旨在确定 导致他们风险增加的潜在因素。神经酰胺是一种脂毒性鞘磷脂， 导致细胞功能障碍，从而导致代谢性疾病。虽然很多文献都在暗示 代谢性疾病中的神经酰胺主要集中在基因的遗传修饰或药物抑制上 在不同的模型系统中，神经酰胺的积累也参与了神经酰胺的合成途径 在人类疾病中表现出来。人类神经酰胺增多的潜在机制 然而，疾病是未知的。作为我们利用犹他大学独特资源进行研究的一部分， 包括犹他州糖尿病数据库和犹他州人口数据库，我们最近发现了罕见的突变 这会改变两个富含肥胖症、糖尿病和终末期肾病的家庭的神经酰胺水平，导致 家族性神经酰胺障碍症，包括来自太平洋岛屿的第一个与罕见基因变异相关的家庭 神经酰胺升高。鉴于这一新的和重要的发现，我们假设异常的鞘脂 改变其生物合成的水平和遗传变异是代谢性疾病和相关疾病的关键因素 PI中的合并症。基于这一证据，这个发展研究项目的目标是扩大 本研究利用多组学方法研究和探讨鞘脂水平在PI代谢性疾病中的作用 这一方法包括对大型、多代PI家系进行脂质学和基因组分析。至 为了实现这一目标，我们将1)测定25只大型、多代猪的鞘脂水平 通过i)扩大目前在犹他州登记的PI家庭的招募，获得代谢性疾病家系 糖尿病和糖尿病并发症研究，每个家庭至少包括10-15名成员，以及ii)使用液体 层析-串联质谱法建立所有招募人员中鞘磷脂物种的脂谱 PI家族成员和2)评估遗传变异对PI家族成员鞘脂水平的贡献 大的多世代PI家系的研究--I)异常的PI家系成员的遗传变异筛选 鞘磷脂全外显子组测序和II)进行统一连锁分析和罕见变异 关联性测试，以确定影响鞘磷脂物种的变异。我们预计这项研究将 建立在令人兴奋的初步数据基础上，并就此途径在代谢性疾病中的作用提供关键见解 PIS.这项研究将为未来旨在阐明背后机制的努力提供坚实的基础 代谢性疾病在PI中的差异，并有助于将这些发现转化为改进的诊断和 治疗学。