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: 10462627
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 19.06万
• 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/10462627
• 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 Islander; 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.

项目摘要 太平洋岛民（PIS）具有全球最高的代谢疾病负担，并且正在增加 其他相关合并症的风险，例如心血管疾病，肾脏疾病和癌症。尽管 这些复杂疾病的高率很大，PI在旨在识别的研究中大大不足。 导致其风险增加的基本因素。神经酰胺是脂肪毒性鞘脂的 导致导致代谢疾病的细胞功能障碍。而许多文献隐含 代谢性疾病中的神经酰胺以基因的遗传修饰或药理抑制为中心 参与各种模型系统中的神经酰胺合成途径，神经酰胺的积累也一直是 在人类疾病中证明。导致人类神经酰胺增加的基本机制 但是，疾病尚不清楚。作为我们利用犹他大学独特资源的研究的一部分， 包括犹他州糖尿病数据库和犹他州人口数据库，我们最近确定了稀有突变 改变了肥胖，糖尿病和终末期肾脏疾病的2个家庭中的神经酰胺水平，导致 家庭障碍性血症，包括来自太平洋岛屿的第一家家庭，具有罕见的遗传变异 升高的神经酰胺。鉴于这一小说而重要的发现，我们假设这种异常的鞘脂 改变其生物合成的水平和遗传变异是代谢疾病和相关的关键因素 PIS合并症。在此证据的基础上，该发展研究项目的目标是扩大 这项研究并研究了鞘脂水平在PI中使用多媒体的代谢疾病中的作用 大型多代PI谱系的脂质组和基因组分析的方法。到 实现这一目标，我们将1）确定25个大，多代PI的成员的鞘脂水平 i）扩大目前在犹他州入学的PI家族的招募来代谢性疾病 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，ii）使用液体 带有串联质谱的色谱法，在所有招募 PI家族成员和2）评估遗传变异对鞘脂水平的贡献 i）筛选具有异常PI家族成员的遗传变异的大型多代PI谱系 使用整个外显子组测序和ii）进行统一的连锁分析和稀有变体 结合测试以鉴定变体会影响鞘脂。我们预计这项研究将会 以令人兴奋的初步数据为基础，并提供有关该途径在代谢疾病中的作用的关键见解 pis。这项研究将为未来的努力旨在阐明背后的机制提供坚实的基础 PIS代谢疾病的差异，并促进这些发现的转化为改善诊断和 疗法。