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.

项目摘要/摘要 先兆子痫在美国3%-6%的妇女中发生，是#年母婴发病率的主要来源。 怀孕后立即怀孕，对母亲和孩子的心血管健康都有长期影响。 先兆子痫母婴分娩后一年内的医疗管理费用平均超过28亿美元 每年1美元。在美国，先兆子痫的患病率正在增加。非裔美国女性拥有更高的 先兆子痫的患病率，更有可能患有严重的先兆子痫，死亡的可能性是白人的三倍 美国人因妊娠相关并发症。到目前为止，尚无有效的子痫前期预防策略 由于缺乏对因果关系的了解--无论是临床风险因素、遗传倾向还是社会中介因素。 流行病学研究确定了多种临床危险因素和先兆子痫的预测因素，如肥胖、糖尿病、 既往有高血压、慢性肾脏疾病和血栓形成。研究还表明，在没有这些的女性中 先兆子痫患者罹患高血压、慢性肾脏疾病、 5到10年后发生静脉血栓栓塞症、中风和糖尿病。推断这些关联的因果关系是很困难的 由于潜在的混淆和反向因果关系，仅有流行病学数据。先兆子痫及其许多危险因素和 它的后果是可遗传的，发现了数百种遗传变异，这些变异导致了一些特征，如血压、糖尿病和 肾功能。因为遗传变异在一生中不会改变，也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，所以不太容易混淆 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，积极评估风险暴露与结果之间的因果关系。合并遗传数据 关于来自多种来源的先兆子痫，并利用Vanderbilt现有的EHR链接生物库(BioVU)，我们形成了 先兆子痫遗传学网络(PEGNet)研究超过28,000例子痫前期患者的遗传结构 病例和超过29万个对照。使用PEGNet的先兆子痫数据和磁共振方法的最新进展，我们 建议评估临床危险因素和包括血液在内的子痫前期预测因素之间的因果关系 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有因果关系 与未来的心血管并发症有关，或者这是由于反向因果关系造成的。随着新兴的磁共振方法，如 作为药物靶点MR，我们建议筛选与子痫前期相关的基因和蛋白质靶点，同时也是可药物的靶点。我们 建议进行磁共振实验以验证正在研发的预防子痫前期的现有药物的基因靶点，包括 阿司匹林、二甲双胍、他汀类药物和PDE5阻滞剂。我们提出了一个新的MR框架来解释色彩主义，一个社会的角色 使用皮肤色素沉着的遗传变异构建基于肤色的子痫前期风险判别 肤色的工具性变量。我们建议混合作图来了解遗传祖先是如何影响 非洲血统妇女的先兆子痫。以创新的方式使用磁共振方法，我们的研究揭示了原因 先兆子痫的机制，是设计有效干预策略所必需的第一步。