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

项目摘要 太平洋岛民（PI）是世界上代谢疾病负担最高的人群之一， 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 这些复杂疾病的发病率很高，在旨在确定 导致其风险增加的潜在因素。神经酰胺是脂毒性鞘脂， 导致细胞功能障碍，导致代谢疾病。虽然许多文献暗示 神经酰胺在代谢性疾病中的应用主要集中在基因修饰或基因的药物抑制上 在各种模型系统中参与神经酰胺合成途径， 在人类疾病中表现出来。导致人体神经酰胺增加的潜在机制 然而，疾病是未知的。作为我们利用犹他州大学独特资源研究的一部分， 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 改变了2个肥胖、糖尿病和终末期肾病家族的神经酰胺水平， 家族性神经酰胺异常症，包括来自太平洋岛屿的第一个家族， 神经酰胺含量升高鉴于这一新的重要发现，我们假设异常鞘脂 改变其生物合成的水平和遗传变异是代谢疾病和相关疾病的关键因素。 PI中的合并症。基于这一证据，这一发展研究项目的目标是扩大 本研究使用多组学方法研究鞘脂水平在PI代谢性疾病中的作用， 方法，包括大型多代PI家系的脂质组学和基因组学分析。到 为了实现这一目标，我们将1）确定25个大型多代PI成员的鞘脂水平 i）扩大招募目前在犹他州登记的PI家族， 糖尿病和糖尿病并发症研究包括每个家庭至少10-15名成员，ii）使用液体 色谱串联质谱法，以建立所有招募的鞘脂种类的脂质谱 PI家族成员和2）评估遗传变异对PI家族成员中鞘脂水平的贡献。 通过i）在具有异常的PI家族的成员中筛选遗传变体， 使用全外显子组测序的鞘脂谱，和ii）进行统一的连锁分析和罕见的变异 相关性测试以鉴定影响鞘脂种类的变体。我们预计，这项研究将 建立在令人兴奋的初步数据，并提供关键的见解，这一途径在代谢疾病中的作用， 私家侦探这项研究将为未来旨在阐明其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，并促进将这些发现转化为改进的诊断， 治疗学

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.