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

基本信息

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
项目类别：
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

项目摘要

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 Precamia发生在美国的3％ - 6％的妇女中，是母亲和胎儿发病率的领先来源怀孕，怀孕后立即对母亲和儿童具有长期心血管健康的影响。在分娩后一年内，先兆子痫的母亲和婴儿的医疗保健管理成本超过28亿美元每年美元。在美国，先兆子痫的患病率正在加班。非洲裔美国妇女的妇女更高先兆子痫的患病率更可能患有严重的先兆子痫，死亡的可能性是白色的三倍由于怀孕与并发症有关的美国人。迄今为止，没有有效的预防性策略的部分由于缺乏因果关系，无论是临床风险因素，遗传易感性还是社会介导的因素。流行病学研究确定了多种临床危险因素ANAD对先兆子痫的谓词，例如肥胖，糖尿病，先前存在的高血压，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的疾病患者患高血压，慢性肾脏疾病的风险更高， 5至10年后，静脉血栓栓塞，中风和糖尿病。这些关联的推断很难仅由于存在混淆和反向原因而导致的流行病学数据。 Preclamsia，其许多风险因素和它的后果是可遗传的，有数百种遗传变异，以鉴定出一些特征，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，并且不能受到反向原因的影响，并且由于门德尔的遗产定律决定了随机分类和隔离，因此不太容易混淆基因，我们可以设计Mendelian Randomiza- （MR）使用遗传变异作为仪器变量的实验在某些假设下，暴露于暴露与结果之间的因果关系。融合遗传数据关于来自多个来源的先兆子痫，并利用范德比尔特的现有EHR连接生物库（BIOVU），我们形成了学位前遗传学网络（PEGNET）研究超过28,000个先兆子痫的先兆子痫的遗传结构案例和超过290,000个控件。使用PEGNET的先兆子痫数据以及MR方法的最新发展，我们评估临床风险因素与先兆子痫的预测因素之间的因果关系的提议，包括血液压力，肾功能，肝功能，肥胖和代谢特征。我们将评估子痫前期是否为因果与未来的心血管并发症相关，或者是由于逆转性而引起的。与新兴的MR方法这样作为药物靶MR，我们建议筛选与先兆子痫和可药物相关的基因和蛋白质靶标。提案MR实验验证基因靶标的基因靶标的现有药物预防先兆子痫预防的药物阿司匹林，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，以阐明角色症的角色，一个社会基于肤色的歧视构建，利用皮肤色素沉着的遗传变异作为前启示性风险的构造肤色的仪器变量。我们建议混合图映射以了解遗传血统如何影响非洲血统妇女的先兆子痫。我们的研究以创新的方式使用MR方法，告知催化先兆子痫的机制，设计有效的干预策略所需的第一步。