Investigating the regulation of central metabolism as key to human health and disorders through the association of PASK, USF1 and ATXN2 with phenotypes and disorders in the All of Us database

代谢失调是大多数疾病的核心，从高脂血症和糖尿病到 癌症和神经退行性疾病。感知细胞代谢物的感觉蛋白激酶 并相应地调节新陈代谢，处于代谢动态平衡的核心。PASK(PASK)是 一种营养感应蛋白激酶，调节葡萄糖到脂肪生产的分配，而不是 呼吸代谢。PASK缺陷小鼠对肝脏甘油三酯积聚和显示具有抵抗力 高脂肪或高脂肪高糖饮食时呼吸增加。此外，PASK缺陷小鼠 在多项研究中显示胰岛素代谢改变，PASK等位基因与成熟开始相关 一项小型家族研究中的青年糖尿病(MODY)。我们的长期目标是确定这个角色的特征 PASK在人类疾病中的作用，包括它调节中枢新陈代谢的分子途径。 我们在这里描述的短期目标是对PASK等位基因进行第一次大规模分析(和 其蛋白质底物的等位基因)与人类疾病有关。 格罗斯实验室已经确定了两种与脂质和呼吸有关的PASK底物 代谢，即上游刺激因子1(USF1)和趋化因子-2(ATXN2)，主要关注的是 我们目前的R15。在这里，分子生物学家朱莉安·格罗斯博士与玛丽·戴维斯博士合作， 生物医学信息学家和人类遗传学家，揭示PASK、USF1和ATXN2的影响 各种人类表型和疾病类别的变异，从高脂血症和糖尿病到 癌症和神经退行性疾病。我们所有人的数据集使这成为可能。我们所有人都提供 来自电子健康记录、基本生命体征、调查、运动数据(例如Fitbit)和COVID的表型- 19个结果，以及全基因组测序。在我们的第一个目标中，我们将分析常见的和罕见的 PASK、USF1和ATXN2的变种与甘油三酯、体重、心血管指标、 锻炼水平和新冠肺炎成绩。在我们的第二个目标中，我们将执行一个现象范围的关联 研究(Phewas)，其中PASK、USF1和ATXN2的变体将根据表型进行回归 从电子健康记录数据。除了各种各样的表型数据外，祖先 数据集中的个体所代表的多样性将使我们能够识别出 在不同的祖先之间不同或相似，识别由于祖先和保守的多基因效应 这是人类共同的影响。综合起来，我们的R15和Informatic的机械结果 这里描述的补充结果进一步推动了我们在整体治疗和 人类疾病的预防措施。

Metabolic dysregulation lies at the heart of most disorders, from hyperlipidemia and diabetes to cancer and neurodegenerative disorders. Sensory protein kinases, which sense cellular metabolites and regulate metabolism accordingly, lie at the heart of metabolic homeostasis. PAS kinase (PASK) is a nutrient sensing protein kinase that regulates partitioning of glucose to lipid production versus respiratory metabolism. PASK deficient mice are resistant to liver triglyceride accumulation and display increased respiration when on a high-fat or high-fat high-sugar diet. In addition, PASK deficient mice display altered insulin metabolism in several studies, with PASK alleles associated with Maturity Onset Diabetes of the Young (MODY) in a small familial study. Our long-term goal is to characterize the role of PASK in human disease, including the molecular pathways by which it regulates central metabolism. Our short-term goal described herein is to conduct the first large-scale analysis of PASK alleles (and alleles of its protein substrates) associated with human disease. The Grose lab has identified two PASK substrates associated with lipid and respiratory metabolism, namely Upstream Stimulatory Factor 1 (USF1) and Ataxin-2 (ATXN2), the primary focus of our current R15. Herein Dr. Julianne Grose, a molecular biologist, teams up with Dr. Mary Davis, a biomedical informaticist and human geneticist, to uncover the influence of PASK, USF1, and ATXN2 variants on a variety of human phenotypes and classes of disease, from hyperlipidemia and diabetes to cancer and neurodegenerative disorders. The All of Us dataset makes this possible. All of Us provides phenotypes from electronic health records, basic vitals, surveys, exercise data (e.g. Fitbit) and COVID- 19 results, as well as whole genome sequencing. In our first Aim we will analyze common and rare variants in PASK, USF1, and ATXN2 compared to triglycerides, weight, cardiovascular measures, exercise levels and COVID-19 results. In our second Aim, we will perform a phenome-wide association study (PheWAS), in which variants in PASK, USF1, and ATXN2 will be regressed against phenotypes from electronic health record data. In addition to the wide variety of phenotypic data, the ancestral diversity represented by the individuals in the dataset will allow us to identify patterns and variants that differ or are similar across ancestry, identifying both multigene effects due to ancestry and conserved effects common to humankind. Combined, the mechanistic results from our R15 and the informatic results from the supplement described herein further our progress towards holistic treatments and preventions for human disorders.