Understanding causal mechanisms in preeclampsia through genetic instrumental variables

通过遗传工具变量了解先兆子痫的因果机制

• 批准号: 10345097
• 负责人: Ayush Giri
• 金额: $ 78.95万
• 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: 2022-01-05 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345097
• 关键词: Admixture; Affect; African American; African ancestry; American; Aspirin; Benefits and Risks; Birth; Blood Pressure; Boston; Cardiovascular system; Child; Chronic Kidney Failure; Clinical; Cohort Studies; Collection; Color; Data; Development; Diabetes Mellitus; Discrimination; Drug Targeting; Drug usage; Epidemiologic Methods; Epidemiology; Etiology; European; Exposure to; Fetal Death; Fetus; Future; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; Health; Health Care Costs; Heritability; High Prevalence; Hypertension; Incidence; Infant; Intervention; Investigational Drugs; Laws; Link; Lipids; Maps; Measures; Mediating; Mendelian randomization; Meta-Analysis; Metabolic; Metabolic dysfunction; Metformin; Methods; Morbidity - disease rate; Mothers; Myocardial Ischemia; Obesity; Outcome; Patient Self-Report; Pharmaceutical Preparations; Pharmacologic Substance; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Prevalence; Prevention; Prevention strategy; Proteins; Proxy; Public Health; Race; Renal function; Research; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Severities; Skin; Skin Pigmentation; Social Environment; Socioeconomic Status; Source; Stress; Stroke; Structure; Thrombophilia; Time; Validation; Vascular Endothelium; Woman; admixture mapping; base; biobank; cardiovascular health; caucasian American; clinical risk; design; disparities in morbidity; drug discovery; drug repurposing; early onset; effective intervention; epidemiologic data; epidemiology study; experimental study; fetal; flexibility; gene discovery; genetic architecture; genetic resource; genetic variant; genome wide association study; health management; high risk; high throughput screening; innovation; insight; instrument; liver function; mortality; multiple omics; novel; phenome; protein expression; racial disparity; racism; risk stratification; risk variant; segregation; side effect; skin color; social; social relationships; statistics; theories; trait; venous thromboembolism

PROJECT SUMMARY/ABSTRACT Preeclampsia occurs in 3% – 6% of women in the US and is a leading source of maternal and fetal morbidity during pregnancy, immediately after pregnancy and has long term cardiovascular health implications for both mother and child. Cost of healthcare management of preeclamptic mothers and infants within one year of delivery averages over $2.8 billion dollars annually. Prevalence of preeclampsia is increasing overtime in the US. African American women have higher prevalence of preeclampsia, are more likely to have severe preeclampsia and are three times as likely to die as white Americans due to pregnancy related complications. No effective preventative strategy for preeclampsia exists to-date in part due to a lack of understanding of causality – be it clinical risk factors, genetic predisposition or socially mediated factors. Epidemiological studies identify multiple clinical risk factors anad predictors for preeclampsia such as obesity, diabetes, preexisting hypertension, chronic kidney disease, and thrombophilia. Studies also show that in women without these preexisting conditions, those with preeclampsia are at higher risk of developing hypertension, chronic kidney disease, venous thromboembolism, stroke and diabetes 5 to 10 years later. Inferring causality for these associations is difficult with epidemiologic data alone due to potential for confounding and reverse causation. Preeclampsia, many of its risk factors and its consequences are heritable with hundreds of genetic variants identified for some traits like blood pressure, diabetes and kidney function. Since genetic variants do not change during a lifetime and cannot be influenced by reverse causation, and are less prone to confounding due to Mendel's laws of inheritance which dictate random assortment and segregation of genes, we can design Mendelian randomization (MR) experiments to use genetic variants as instrumental variables for exposures to robustly evaluate causality between exposure and outcome under certain assumptions. Coalescing genetic data on preeclampsia from multiple sources and leveraging existing EHR-linked biobank (BioVU) at Vanderbilt, we form the PreEclampsia Genetics Network (PEGNet) to study the genetic architecture of preeclampsia in over 28,000 preeclampsia cases and over 290,000 controls. Using preeclampsia data from PEGNet and recent developments in MR methods, we propose to evaluate causal relationships between clinical risk factors and predictors of preeclampsia including blood pressure, kidney function, liver function, obesity and metabolic traits. We will evaluate whether preeclampsia is causally associated with future cardiovascular complications or if this is due to reverse causality. With emerging MR methods such as drug target MR, we propose to screen gene and protein targets associated with preeclampsia and also druggable. We propose MR experiments to validate gene targets for existing drugs in the pipeline for preeclampsia prevention including aspirin, metformin, statins, and PDE5 blockers. We propose a novel MR framework to elucidate the role colorism, a social construct of discrimination based on skin color, on preeclampsia risk by using genetic variants of skin pigmentation as instrumental variables for skin tone. We propose admixture mapping to understand how genetic ancestry influences preeclampsia in women of African ancestry. Using MR methods in innovative ways, our research informs causal mechanisms in preeclampsia, the first step necessary to design effective intervention strategies.

项目概要/摘要 在美国，有 3% – 6% 的女性患有先兆子痫，是孕产妇和胎儿发病的主要原因。 怀孕、怀孕后立即服用，对母亲和孩子都有长期的心血管健康影响。 先兆子痫母亲和产后一年内婴儿的医疗保健管理成本平均超过 28 亿美元 美元每年。在美国，先兆子痫的患病率正在不断增加。非裔美国女性拥有更高的 先兆子痫的患病率更高，更有可能患有严重的先兆子痫，并且死亡的可能性是白人的三倍 美国人由于怀孕相关并发症。迄今为止，部分先兆子痫尚无有效的预防策略 由于缺乏对因果关系的理解——无论是临床风险因素、遗传倾向还是社会介导因素。 流行病学研究确定了先兆子痫的多种临床危险因素和预测因子，例如肥胖、糖尿病、 既往患有高血压、慢性肾病和血栓形成倾向。研究还表明，在没有这些的女性中 患有先兆子痫的人患高血压、慢性肾病的风险较高， 5至10年后静脉血栓栓塞、中风和糖尿病。推断这些关联的因果关系很困难 由于存在混杂和反向因果关系的可能性，仅使用流行病学数据。先兆子痫及其许多危险因素和 其后果是可遗传的，针对某些特征（例如血压、糖尿病和 肾功能。由于遗传变异在一生中不会改变，并且不会受到反向因果关系的影响，并且 由于孟德尔遗传定律规定了随机分类和分离，因此不太容易混淆 基因，我们可以设计孟德尔随机化（MR）实验，使用遗传变异作为工具变量 在某些假设下，稳健地评估暴露与结果之间的因果关系。合并遗传数据 针对来自多个来源的先兆子痫并利用范德堡大学现有的 EHR 相关生物库 (BioVU)，我们组建了 先兆子痫遗传学网络 (PEGNet) 将研究 28,000 多名先兆子痫患者的先兆子痫遗传结构 病例和超过 290,000 个对照。利用来自 PEGNet 的先兆子痫数据和 MR 方法的最新发展，我们 提议评估临床危险因素和先兆子痫的预测因素（包括血液）之间的因果关系 压力、肾功能、肝功能、肥胖和代谢特征。我们将评估先兆子痫是否是因果关系 与未来的心血管并发症相关，或者这是由于反向因果关系造成的。随着新兴的 MR 方法，例如 作为药物靶点MR，我们建议筛选与先兆子痫相关且可药物化的基因和蛋白质靶点。我们 提出 MR 实验来验证现有药物的基因靶标，用于预防先兆子痫，包括 阿司匹林、二甲双胍、他汀类药物和 PDE5 阻滞剂。我们提出了一个新颖的 MR 框架来阐明色彩主义的作用，这是一种社会现象 通过使用皮肤色素沉着的遗传变异作为先兆子痫风险，构建基于肤色的歧视 肤色的工具变量。我们提出混合图谱来了解遗传血统如何影响 非洲血统女性的先兆子痫。我们的研究以创新的方式使用 MR 方法，为因果关系提供信息 先兆子痫的机制，设计有效干预策略所需的第一步。