Risk stratification in pulmonary arterial hypertension: Intersection of OMICs and longitudinal phenotypes through the PAH Biobank

肺动脉高压的风险分层：通过 PAH 生物库的 OMIC 和纵向表型的交叉点

• 批准号: 10688099
• 负责人: Ankit A Desai
• 金额: $ 79万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688099
• 关键词: Address; African American population; Alleles; Attenuated; BMPR2 gene; Biological; Biology; Candidate Disease Gene; Cell physiology; Cessation of life; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cohort Studies; Data; Data Reporting; Data Set; Development; Disease Outcome; Disease Progression; Endothelial Cells; Endothelium; Enhancers; Ethnic Origin; Ethnic Population; European; European ancestry; Female; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Diseases; Genetic Variation; Genotype; Goals; HLA-DPB1 gene; HMG-Box Domains; Health; Heritability; Hispanic Populations; Histocompatibility Antigens Class II; Histology; Human; Hypoxia; Inflammation; Inflammatory; Interleukin-1; International; Lead; Link; Lung; Mass Spectrum Analysis; Mediating; Meta-Analysis; Metabolic; Minority; Minority Groups; Mitochondria; Modeling; Multiomic Data; Mus; Mutation; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population Heterogeneity; Preclinical Testing; Prognosis; Publishing; Pulmonary Vascular Resistance; Quantitative Trait Loci; R24; Registries; Regulation; Reporting; Risk; Risk Factors; Rodent; Role; SOX17 gene; Smooth Muscle; Smooth Muscle Myocytes; Spain; Testing; Time; Validation; Variant; Vital Status; Whole Blood; anakinra; arteriole; biobank; clinical risk; cohort; disorder risk; exome sequencing; genetic association; genetic variant; genome wide association study; genome-wide; genomic locus; hypertension control; hypertension treatment; improved; inhibitor; insight; metabolomics; mortality; new therapeutic target; novel; overexpression; precision medicine; predict clinical outcome; pulmonary arterial hypertension; rare condition; rare variant; response; right ventricular failure; risk stratification; risk variant; therapeutic target; tool; transcription factor; transcriptome sequencing; treatment response; whole genome

Pulmonary arterial hypertension (PAH) is a rare, fatal condition characterized by the gradual occlusion of the pulmonary arterioles leading to progressively increased pulmonary vascular resistance with worsening right heart failure and death. While rare mutations (e.g., in BMPR2) have been reported in a minority of patients, most patients carry no established mutations. We recently published on common genetic variation in 2,085 idiopathic/heritable (I/H) PAH cases and 9,659 controls of European ancestry using a genome-wide association (GWA) approach. Discovery and replication analyses were conducted in four independent cohorts with genotyping arrays from our US-based PAH Biobank (PAHB) study and three international cohorts with whole genome sequence data. We reported two novel loci, at HLA-DPA1/DPB1 and near SOX17 associated I/H PAH. HLA-DPA/DPB1 locus predicts a reduced annual mortality rate by 25-37% in I/H PAH. The lead SOX17 variant is located in a putative enhancer region in close spatial proximity to the SOX17 gene in endothelial cell (EC) precursors, which influences its expression based on our experimental validation. Our findings provide the first support for the contribution of common genetic variance to PAH risk and, combined with the recently reported data on rare mutations in SOX17 in PAH, highlight the causal role of SOX17 in PAH. Beyond PAH risk, we now hypothesize that PAH progression and outcomes are also genetically modified including from SOX17, a transcription factor, and HLA-DPA1/DPB1 as both novel candidate genes and possible therapeutic targets. To test this hypothesis, we have developed 3 specific aims (SAs) that will further expand the PAHB, the world’s largest PAH biobank, registry, and multi-omics dataset with whole exome sequencing (WES), RNAseq, whole genome genotyping, and non-targeted metabolomics data on nearly all subjects. SA #1 will collect serial longitudinal data in PAHB to interrogate associations between disease risk loci (SOX17, HLA-DPA/B1) with markers of PAH progression. We will also evaluate expression (eQTL) and metabolomics (mQTL) quantitative trait loci analyses for functional validation. Beyond disease risk SOX17/HLA loci, we generated additional preliminary data revealing genome-wide significance for seven novel genetic loci associated directly with survival in PAH in a second, independent PAH cohort. SA #2 will now replicate these new findings with outcomes (progression and survival) collected in PAHB from SA #1. As a unique feature of this proposal, we will interrogate our top loci in two other global PAH cohorts with available eQTL and mQTL data and perform a meta-analysis of all cohorts. We will also construct a risk stratification tool combining clinical risk factors and genetics (SOX17, HLA, 7 SNPs) for PAH outcomes. Finally, based on preliminary data on the protective role of SOX17 in EC function, SA #3 will validate the biological role of SOX17 pathway in the development of PAH using ECs/SMCs isolated from PAH patients as well as pre-clinical testing in murine PH models. Strong clinical association of these two new loci has implications for prediction of clinical outcomes, clinical trial design, and the development of novel drug targets.

肺动脉高压（PAH）是一种罕见的致命性疾病，其特征是肺动脉逐渐闭塞， 肺小动脉导致肺血管阻力进行性增加伴右心恶化 失败和死亡。虽然罕见的突变（例如，在BMPR 2中）在少数患者中报告，大多数 患者没有携带已确定的突变。我们最近发表了关于2085年常见遗传变异的文章， 使用全基因组关联的欧洲血统的特发性/遗传性（I/H）PAH病例和9，659例对照 (GWA)approach.发现和复制分析在四个独立的队列中进行， 来自我们美国PAH生物库（PAHB）研究的基因分型阵列和三个国际队列， 基因组序列数据。我们报告了两个新的位点，在HLA-DPA 1/DPB 1和近SOX 17相关的I/H PAH。 HLA-DPA/DPB 1基因座预测I/H PAH患者的年死亡率降低25-37%。领先的SOX 17变体 位于内皮细胞（EC）中与SOX 17基因空间接近的推定增强子区域 前体，这影响其表达的基础上，我们的实验验证。我们的发现提供了第一个 支持常见遗传变异对PAH风险的贡献，结合最近报告的 关于PAH中SOX 17罕见突变的数据，突出了SOX 17在PAH中的因果作用。除了PAH风险，我们现在 假设PAH进展和结局也是基因修饰的，包括来自SOX 17， 转录因子和HLA-DPA 1/DPB 1作为新的候选基因和可能的治疗靶点。到 为了验证这一假设，我们制定了3个具体目标（SA），将进一步扩大PAHB，世界上 最大的PAH生物库、注册表和多组学数据集，包括全外显子组测序（WES）、RNAseq、全 几乎所有受试者的基因组基因分型和非靶向代谢组学数据。SA #1将收集序列号 PAHB中的纵向数据，以询问疾病风险位点（SOX 17，HLA-DPA/B1）与 PAH进展的标志物。我们还将评估表达（eQTL）和代谢组学（mQTL）数量性状 用于功能验证的基因座分析。除了疾病风险SOX 17/HLA基因座，我们还产生了额外的初步研究结果。 数据揭示了与PAH生存率直接相关的7个新遗传基因座的全基因组意义， 第二个独立PAH队列。SA #2现在将复制这些新的结果（进展和 存活）收集于来自SA#1的PAHB中。作为本提案的一个独特之处，我们将在两个方面询问我们的顶级场所， 其他全球PAH队列与可用的eQTL和mQTL数据，并对所有队列进行荟萃分析。我们将 还构建了结合临床危险因素和遗传学（SOX 17、HLA、7个SNP）的PAH风险分层工具 结果。最后，基于SOX 17在EC功能中的保护作用的初步数据，SA #3将验证 使用从PAH患者中分离的EC/SMCs研究SOX 17通路在PAH发生中的生物学作用 以及在鼠PH模型中的临床前测试。这两个新基因座的强临床相关性 对临床结果预测、临床试验设计和新药靶点开发的意义。

项目成果

Germline and Somatic Mutations in DNA Methyltransferase 3A (DNMT3A) Predispose to Pulmonary Arterial Hypertension (PAH) in Humans and Mice: Implications for Associated PAH.

DNA 甲基转移酶 3A (DNMT3A) 的种系和体细胞突变易导致人和小鼠肺动脉高压 (PAH)：对相关 PAH 的影响。

• DOI: 10.1101/2023.12.30.23300391
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Al-Qazazi,Ruaa;Emon,IsaacM;Potus,François;Martin,AshleyY;Lima,PatriciaDA;Vlasschaert,Caitlyn;Chen,Kuang-Hueih;Wu,Danchen;Gupta,AsishDas;Noordhof,Curtis;Jefferson,Lindsay;McNaughton,AmyJM;Bick,AlexanderG;Pauciulo,Michael
• 通讯作者: Pauciulo,Michael

Low-affinity insulin-like growth factor binding protein 7 and its association with pulmonary arterial hypertension severity and survival.

• DOI: 10.1002/pul2.12284
• 发表时间: 2023-07
• 期刊: PULMONARY CIRCULATION
• 影响因子: 2.6
• 作者: Torres, Guillermo;Lancaster, Andrew C.;Yang, Jun;Griffiths, Megan;Brandal, Stephanie;Damico, Rachel;Vaidya, Dhananjay;Simpson, Catherine E.;Martin, Lisa J.;Pauciulo, Michael W.;Nichols, William C.;Ivy, David D.;Austin, Eric D.;Hassoun, Paul M.;Everett, Allen D.
• 通讯作者: Everett, Allen D.