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

项目概要 太平洋岛民 (PI) 是世界上代谢疾病负担最高的人群之一，并且其患病率也在不断增加 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 由于这些复杂疾病的发病率很高，PI 在旨在识别疾病的研究中基本上没有得到充分体现。 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。虽然很多文献都暗示 神经酰胺在代谢疾病中的作用主要集中在基因修饰或基因的药理抑制上 参与各种模型系统中的神经酰胺合成途径，神经酰胺的积累也已被证实 在人类疾病中得到证实。导致人体神经酰胺增加的潜在机制 然而，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，我们最近发现了罕见突变 改变两个患有肥胖症、糖尿病和终末期肾病的家庭的神经酰胺水平，导致 家族性神经酰胺血症，包括来自太平洋岛屿的第一个家族，该家族患有与此相关的罕见遗传变异 具有升高的神经酰胺。鉴于这一新颖且重要的发现，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疾病和相关疾病的关键因素 PI 中的合并症。在此证据的基础上，该开发研究项目的目标是扩大 这项研究并使用多组学研究了鞘脂水平在 PI 代谢疾病中的作用 方法包括对大型多代 PI 谱系进行脂质组学和基因组分析。至 为了实现这一目标，我们将 1) 测定 25 名大型多代 PI 成员中的鞘脂水平 i) 扩大目前在犹他州注册的 PI 家族的招募范围 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，并且 ii) 使用液体 色谱法与串联质谱法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 家族成员鞘脂水平的贡献 大型、多代 PI 谱系，通过 i) 筛查具有异常的 PI 家族成员的遗传变异 使用全外显子组测序进行鞘脂谱分析，并且 ii) 执行统一连锁分析和罕见变异 关联测试以确定影响鞘脂种类的变异。我们预计这项研究将 以令人兴奋的初步数据为基础，并提供关于该途径在代谢疾病中的作用的关键见解 PI。这项研究将为未来旨在阐明其背后机制的努力奠定坚实的基础。 PI 中代谢疾病的差异，并促进将这些发现转化为改进的诊断和 疗法。

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.