Genetics and Triglycerides: opportunities for new approaches to identify therapies

遗传学和甘油三酯：确定治疗方法的新方法的机会

• 批准号: 10445161
• 负责人: Qiping Feng
• 金额: $ 81.97万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445161
• 关键词: 20 year old; ANGPTL3 gene; ANGPTL4 gene; Academic Medical Centers; Adverse effects; Affect; African American population; African ancestry; American; Area; Biological Process; Candidate Disease Gene; Cause of Death; Cessation of life; Computerized Medical Record; Coronary heart disease; Data; Data Set; Databases; Development; Diabetes Mellitus; Disease; Drug Targeting; Electronic Health Record; European; Gene Expression; Genes; Genetic; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genotype; Hypertriglyceridemia; Individual; Knowledge; LDL Cholesterol Lipoproteins; Link; Long-Term Effects; Marketing; Measures; Mendelian randomization; Obesity; Pancreatitis; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Plasma; Proxy; Research; Risk; Sampling; Sampling Studies; Signal Transduction; Tail; Testing; Time; Tissues; Triglycerides; Variant; biobank; clinical phenotype; diabetes risk; disorder prevention; drug candidate; drug development; drug repurposing; exome; exome sequencing; gene function; genetic approach; genetic variant; genome sequencing; genome wide association study; inhibitor; interest; lipoprotein lipase; neglect; new therapeutic target; novel; novel strategies; novel therapeutics; pleiotropism; prevent; rare variant; trait; transcriptome; transcriptomics; virtual; whole genome

Lowering TGs to reduce the risk of coronary heart disease (CHD) is an active area of drug development. New drugs under development target TG genes in the lipoprotein lipase (LPL). The status quo is that: (1) we know little about potential beneficial and detrimental effects of long-term inhibition (or activation) of these target TG genes; (2) most TG-lowering drugs in development focus on the LPL pathway--we need to identify new TG targets in other pathways; (3) TG drug development currently targets one gene at a time and neglects agents that affect many genes simultaneously. We propose to fill the knowledge gaps as follows. (1) TG levels are associated with many diseases and TG genes regulate many biological processes; thus, long-term targeting of TG genes may have pleiotropic effects other than reducing CHD. Traditional post- marketing approaches to identify such effects require a long time. The effects of long-term inhibition of TG genes can be defined rapidly by studying individuals with genetically determined variation in gene function--a Mendelian randomization approach. In Aim 1 we will define clinical phenotypes other than CHD associated with genetically determined variation of TG gene function by using (a) known functional variants, (b) imputed gene expression, and (c) a gene-specific genetic risk score (GRS) as proxies of long-term effect of drugs targeting TG genes (LPL, APOC2, APOC3, ANGPTL3, and ANGPTL4) and testing their association with ~1,600 clinical phenotypes extracted from EHRs in BioVU (~130,000) and eMERGE (~100,000). (2) Identifying novel genes associated with TG levels will facilitate the development of TG-lowering drugs. The high genetic diversity in people of African ancestry (AAs) enhances our ability to identify variants with large effect size. A strategy of combining sequencing and extreme-tail sampling (studying people at the extremes of a quantitative trait) led to the development of PCSK9 inhibitors to lower LDL-C. In Aim 2, we will apply extreme- tail sampling and exome sequencing in AAs to identify new therapeutic targets for lowering TGs. (3) In addition to targeting one gene at a time, there is increasing interest in using the transcriptome for drug development by searching for drugs that reverse the transcriptomic signature associated with a disease. However, the measured transcriptome is affected by the disease itself and associated diseases and therapies. In contrast, the genetic component of the transcriptome is not confounded in this way and is more likely to represent a causal signal. In Aim 3, we will impute the genetically determined component of the TG transcriptome (i.e., the virtual transcriptome). By searching drug perturbation databases, we will identify repurposing drug candidates that reverse the TG virtual transcriptomic signature. The candidates identified will be validated by characterizing their effects on measured TGs in large EHRs (BioVU and eMERGE). These studies will have potential high impact by identifying: 1) new uses and new adverse effects of TG-lowering drugs in development; 2) new genetic targets for TG lowering; 3) existing drugs that lower TGs.

降低甘油三酯以降低冠心病 (CHD) 风险是药物开发的一个活跃领域。新的 正在开发的药物针对脂蛋白脂肪酶 (LPL) 中的 TG 基因。现状是：（1）我们知道 很少涉及长期抑制（或激活）这些目标 TG 的潜在有益和有害影响 基因； (2) 大多数正在开发的降TG药物集中在LPL途径——我们需要识别新的TG 其他途径中的目标； (3) TG药物开发目前只针对一个基因而忽略了药物 同时影响许多基因。我们建议填补以下知识空白。 (1) TG水平与多种疾病相关，TG基因调节多种生物过程； 因此，长期靶向TG基因除了可以减少冠心病之外，还可能具有多效性作用。传统的后 营销方法要识别这种效果需要很长时间。长期抑制TG的影响 通过研究具有遗传决定的基因功能变异的个体，可以快速定义基因 孟德尔随机化方法。在目标 1 中，我们将定义除 CHD 相关之外的临床表型 通过使用（a）已知的功能变异，（b）估算的 TG 基因功能的遗传决定变异 基因表达，以及 (c) 基因特异性遗传风险评分 (GRS) 作为药物长期效应的代理 靶向 TG 基因（LPL、APOC2、APOC3、ANGPTL3 和 ANGPTL4）并测试它们与 从 BioVU（约 130,000）和 eMERGE（约 100,000）中的 EHR 中提取约 1,600 种临床表型。 (2)鉴定与TG水平相关的新基因将有助于降低TG药物的开发。 非洲血统人群 (AA) 的高度遗传多样性增强了我们识别具有大变异的能力 效应大小。结合测序和极端尾部采样的策略（研究处于极端情况的人） 数量性状）导致了 PCSK9 抑制剂的开发，以降低 LDL-C。在目标 2 中，我们将应用极端- AA 中的尾部取样和外显子组测序，以确定降低 TG 的新治疗靶点。 (3) 除了一次靶向一个基因之外，人们对使用转录组进行研究越来越感兴趣 通过寻找逆转与疾病相关的转录组特征的药物来开发药物。 然而，测量的转录组受到疾病本身以及相关疾病和治疗的影响。 相反，转录组的遗传成分不会以这种方式混淆，并且更有可能 代表因果信号。在目标 3 中，我们将估算 TG 的遗传决定成分 转录组（即虚拟转录组）。通过搜索药物扰动数据库，我们将识别 重新利用逆转 TG 虚拟转录组特征的候选药物。确定的候选人将 通过表征它们对大型 EHR（BioVU 和 eMERGE）中测量的 TG 的影响来进行验证。 这些研究将通过确定以下方面产生潜在的重大影响：1）新用途和新的不利影响 正在开发的降TG药物； 2）降低TG的新基因靶点； 3）现有的降低TG的药物。