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TG以降低冠心病（CHD）的风险是药物发育的活跃领域。新的 发育中的药物脂蛋白脂肪酶（LPL）中的靶标TG基因。现状是：（1）我们知道 几乎没有关于这些目标TG的长期抑制（或激活）的潜在有益和有害影响 基因； （2）开发中的大多数降低TG药物都集中在LPL途径上 - 我们需要识别新的TG 其他途径中的目标； （3）TG药物开发目前一次靶向一个基因，而忽略了代理 这同时影响许多基因。我们建议填补以下知识空白。 （1）TG水平与许多疾病和TG基因有关，调节许多生物学过程； 因此，除了降低冠心病之外，TG基因的长期靶向可能具有多效效应。传统帖子 - 识别这种效果的营销方法需要很长时间。长期抑制TG的影响 可以通过研究具有基因功能遗传确定变异的个体来迅速定义基因 - a 孟德尔随机方法。在AIM 1中，我们将定义除CHD相关的临床表型 通过使用（a）已知的功能变异，（b）估算的TG基因函数的遗传确定变异 基因表达和（c）基因特异性遗传风险评分（GRS）作为药物长期影响的代理 靶向TG基因（LPL，APOC2，APOC3，ANGPTL3和ANGPTL4）并测试其与 〜从Biovu（〜130,000）和出现（〜100,000）中提取的EHR提取的〜1,600次临床表型。 （2）识别与TG水平相关的新基因将有助于降低TG的药物的发展。 非洲血统（AAS）的高遗传多样性增强了我们识别大型变体的能力 效果大小。结合测序和极端尾巴采样的策略（在一个极端研究人员 定量性状）导致PCSK9抑制剂的发展降低了LDL-C。在AIM 2中，我们将应用极端 在AAS中进行尾巴采样和外显子组测序，以识别降低TG的新治疗靶标。 （3）除了一次靶向一个基因外，还对使用转录组的兴趣越来越 通过寻找扭转与疾病相关的转录组特征的药物来开发药物。 但是，测得的转录组受疾病本身以及相关疾病和疗法的影响。 相反，转录组的遗传成分并不是这样混淆的，更可能 代表因果信号。在AIM 3中，我们将估算TG的遗传确定成分 转录组（即虚拟转录组）。通过搜索药物扰动数据库，我们将确定 重新利用逆转TG虚拟转录组签名的候选药物。确定的候选人将 通过表征它们对大EHR（BIOVU和出现）中测得的TG的影响来验证。 这些研究将通过识别来产生潜在的高影响：1）新用途和新的不良影响 开发中降低TG的药物； 2）降低TG的新遗传靶标； 3）降低TGS的现有药物。