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

基本信息

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
项目类别：
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

项目摘要

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逐渐增加，右心恶化虽然少数患者报告了罕见突变（例如 BMPR2），但大多数患者都出现了失败和死亡。我们最近发表了关于 2,085 例常见遗传变异的文章。使用全基因组关联分析特发性/遗传性 (I/H) PAH 病例和 9,659 例欧洲血统对照（GWA）方法在四个独立队列中进行了发现和复制分析。来自我们位于美国的 PAH 生物库 (PAHB) 研究和三个国际队列的基因分型芯片我们报告了两个新的基因座，位于 HLA-DPA1/DPB1 和 SOX17 附近相关的 I/H PAH。 HLA-DPA/DPB1 位点预测 I/H PAH 的年死亡率会降低 25-37%。位于内皮细胞 (EC) 中与 SOX17 基因在空间上非常接近的推定增强子区域前体，根据我们的实验验证，它会影响其表达，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，并结合最近报道的关于 PAH 中 SOX17 罕见突变的数据，强调了 SOX17 在 PAH 风险中的因果作用，我们现在。研究发现 PAH 的进展和结果也经过基因改造，包括 SOX17（一种转录因子和 HLA-DPA1/DPB1 都是新的候选基因和可能的治疗靶点。为了检验这一假设，我们制定了 3 个具体目标 (SA)，这将进一步扩大 PAHB，即世界上最大的 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 SA #1 将收集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。 PAHB 的纵向数据询问疾病风险位点（SOX17、HLA-DPA/B1）与我们还将评估表达 (eQTL) 和代谢组学 (mQTL) 数量性状。除了疾病风险 SOX17/HLA 基因座之外，我们还进行了额外的初步分析。数据揭示了与 PAH 生存直接相关的七个新基因位点的全基因组意义第二个独立的 PAH 队列现在将复制这些新发现及其结果（进展和进展）。生存）从 SA #1 中收集到的 PAHB 作为该提案的一个独特特征，我们将询问两个最高位点。我们将对其他全球 PAH 队列提供可用的 eQTL 和 mQTL 数据，并对所有队列进行荟萃分析。还构建了一个结合临床危险因素和遗传学（SOX17、HLA、7 SNP）的 PAH 风险分层工具最后，根据 SOX17 对 EC 功能的保护作用的初步数据，SA #3 将进行验证。使用从 PAH 患者中分离的 ECs/SMCs 研究 SOX17 通路在 PAH 发生中的生物学作用以及小鼠 PH 模型的临床前测试表明这两个新基因座具有很强的临床关联性。对临床结果预测、临床试验设计和新药物靶点开发的影响。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.