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）是一种罕见的致命状况 肺部小动物，导致肺血管耐药性逐渐增加，遗憾的是右心 失败和死亡。虽然少数患者已经报道了罕见的突变（例如，在BMPR2中），但大多数患者 患者没有建立的突变。我们最近在2,085中发表了关于常见遗传变异的 特发性/遗传性（I/H）PAH病例和9,659个对欧洲血统的控制，使用全基因组关联 （GWA）方法。发现和复制分析是在四个独立人群中进行的 来自我们美国的PAH Biobank（PAHB）研究的基因分型阵列和三个国际人群 基因组序列数据。我们在HLA-DPA1/DPB1和SOX17相关的I/H PAH附近报道了两个新颖的基因座。 HLA-DPA/DPB1基因座预测I/H PAH的年年死亡率降低了25-37％。铅Sox17变体 位于推定的增强子区域，在内皮细胞（EC）中与Sox17基因的空间接近 前体，它基于我们的实验验证影响其表达。我们的发现提供了第一个 支持常见遗传差异对PAH风险的贡献，并与最近报道的 关于PAH中Sox17稀有突变的数据，突出了SOX17在PAH中的因果作用。超越PAH风险，我们现在 假设PAH的进展和结果也经过基因修饰，包括Sox17，A 转录因子和HLA-DPA1/DPB1作为新型候选基因和可能的治疗靶标。到 检验这一假设，我们开发了3个特定目标（SAS），这些目标将进一步扩大PAHB（世界） 最大的PAH Biobank，注册表和多媒体数据集，具有整个外显子组测序（WES），RNASEQ，整个 基因组基因分型和几乎所有受试者的非靶向代谢组学数据。 SA＃1将收集系列 PAHB中的纵向数据询问疾病风险基因座（SOX17，HLA-DPA/B1）之间的关联 PAH进展的标记。我们还将评估表达（EQTL）和代谢组学（MQTL）定量性状 基因座分析功能验证。除了疾病风险SOX17/HLA基因座，我们还产生了额外的初步 数据揭示了与与PAH生存直接相关的七个新型遗传位置的全基因组意义 第二个独立的PAH队列。 SA＃2现在将通过结果复制这些新发现（进展和 生存）从SA＃1收集在PAHB中。作为该提案的独特功能，我们将在两次中询问我们的顶级基因座 其他全球PAH队列具有可用的EQTL和MQTL数据，并对所有队列进行荟萃分析。我们将 还可以为PAH构建合并临床风险因素和遗传因素（SOX17，HLA，7 SNP）的风险分层工具 结果。最后，基于SOX17在EC功能中受保护作用的初步数据，SA＃3将验证 Sox17途径在PAH患者中分离的ECS/SMC在PAH开发中的生物学作用 以及鼠pH模型中的临床前测试。这两个新基因座的强大临床关联 预测临床结果，临床试验设计和新药物靶标的发展的意义。

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.