Search for obesity-associated genes with protective effects on metabolic health

寻找对代谢健康具有保护作用的肥胖相关基因

• 批准号: 9977175
• 负责人: Ruth JF Loos
• 金额: $ 58.16万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977175
• 关键词: Address; Adipose tissue; Affect; Animal Model; Biological; Biological Models; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Research; Data; Dyslipidemias; Endocrine; Etiology; Fatty acid glycerol esters; Gene Expression; General Population; Genes; Genetic; Genome; Genotype; Health; Human; Hypertension; Individual; Knowledge; Larva; Lead; Link; Meta-Analysis; Metabolic; Methods; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Phenotype; Physiological; Prevention; Research Personnel; Risk; Risk Factors; Role; Sample Size; Testing; Thinness; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; Translational Research; Weight; Zebrafish; adipocyte differentiation; base; biobank; cardiometabolic risk; cardiometabolism; causal variant; cell type; design; disorder risk; epigenetic regulation; experimental study; follow-up; genetic variant; genome wide association study; genome-wide; genome-wide analysis; genomic locus; high throughput screening; induced pluripotent stem cell; innovation; insight; lipid biosynthesis; mouse model; obesity genetics; obesity risk; obesity treatment; phenotypic data; protective effect; statistics; stem cell differentiation; trait; transcriptomics; treatment strategy

Obesity is a major risk factor for a number of metabolic and cardiovascular complications. However, a substantial proportion of obese individuals are protected from cardiometabolic complications, despite their excess adiposity (the so-called metabolically healthy obese, MHO). Conversely, not all normal weight individuals are metabolically healthy, despite being lean (the metabolically obese normal weight, MONW). The physiological mechanisms that determine why some obese individuals are protected, and why some normal weight individuals are at risk, are poorly understood, because clinical studies are often too small and methods to test presumed pathways involved are too invasive. Identifying genes and the pathways in which they are implicated provides an alternative strategy to elucidate the biology that underlies the MHO and MONW. Genome-wide association studies (GWAS) have so far identified >300 loci for obesity traits. However, these loci have provided only limited insight into the mechanisms that link obesity and its complications, because the GWAS examine each trait in isolation and ignore the fact that obesity is a heterogeneous clinical condition. Therefore, we propose to [1] perform a multi-trait genome-wide search for obesity-increasing loci with protective effects on cardiometabolic traits and vice versa, [2] prioritize candidate genes within identified loci, and [3] functionally characterize prioritized candidate genes in model systems. Specifically, we apply two complementary discovery approaches. In the first approach (Aim 1a), we perform multi-trait correlated meta-analyses that combine summary statistics of adiposity and cardiometabolic GWAS from large-scale genetic consortia and the UK Biobank (Ntotal~840,000). We aim to identify SNPs simultaneously associated with increased adiposity and a favorable cardiometabolic risk profile, and vice versa. In the second approach (Aim 1b), we use individual-level data from the UKBiobank (N~500,000) to perform GWAS on new outcomes derived from the difference between a cardiometabolic and an adiposity trait. Next, we prioritize the most likely candidate genes in identified loci and the most relevant tissues using functional annotation pipelines (Aim 2a) and high-throughput screens in transgenic CRISPR-Cas9-based zebrafish model systems (Aim 2b). Lastly, we investigate the functional impact of prioritized genes using CRISPR-Cas9 in human-induced pluripotent stem cells (hiPSCs) differentiated into relevant cell types (Aim 3a) and tissue-specific transcriptomic analyses in transgenic zebrafish model systems (Aim 3b). Our focus on obesity-associated loci with protective effects on health (and vice versa) is unique and targets a biology that has not been accessed with single-trait GWAS. Our approaches that use model systems to prioritize and characterize genes are innovative and will provide the critical insights needed for in-depth follow- up in murine models and clinical studies. Some identified genes may point towards actionable targets for the prevention and treatment of obesity and its complications with clinical impact for the general population.

肥胖是许多代谢和心血管并发症的主要危险因素。但 相当大比例的肥胖个体被保护免于心脏代谢并发症，尽管他们 过度肥胖（所谓的代谢健康肥胖，MHO）。相反，并非所有正常体重 个体代谢健康，尽管是瘦的（代谢性肥胖正常体重，MONW）。的 生理机制决定了为什么一些肥胖个体受到保护，为什么一些正常的 体重个体处于危险之中，人们对此知之甚少，因为临床研究往往太小， 来测试推测的相关途径太具侵入性了识别基因及其作用途径 牵连提供了一个替代的策略，以阐明生物学的基础MHO和MONW。 全基因组关联研究（GWAS）迄今已确定了超过300个肥胖性状的基因座。但这些 基因位点只能提供有限的了解肥胖及其并发症的联系机制，因为 GWAS孤立地检查每一个特征，忽略了肥胖是一种异质性临床状况的事实。 因此，我们建议[1]对肥胖增加基因座进行多性状全基因组搜索， 对心脏代谢性状的保护作用，反之亦然，[2]优先考虑已鉴定基因座内的候选基因， 和[3]在功能上表征模型系统中的优先候选基因。 具体来说，我们采用两种互补的发现方法。在第一种方法（目标1a）中，我们执行 结合肥胖和心脏代谢GWAS的联合收割机汇总统计的多性状相关荟萃分析 来自大规模遗传财团和英国生物库（Ntotal~ 840，000）。我们的目标是识别SNPs 同时与肥胖增加和有利的心脏代谢风险特征相关， 亦然在第二种方法（目标1b）中，我们使用来自英国生物银行的个人水平数据（N~ 500，000）， 对来自心脏代谢和肥胖特征之间差异的新结果进行GWAS。 接下来，我们优先考虑最有可能的候选基因在确定的基因座和最相关的组织使用 功能注释管道（Aim 2a）和基于转基因CRISPR-Cas9的高通量筛选 斑马鱼模型系统（Aim 2b）。最后，我们研究了优先基因的功能影响， CRISPR-Cas9在人诱导多能干细胞（hiPSC）中分化成相关细胞类型（Aim 3a） 和转基因斑马鱼模型系统中的组织特异性转录组学分析（Aim 3b）。 我们专注于对健康具有保护作用的肥胖相关位点（反之亦然）是独特的， 这是一种尚未通过单一性状GWAS获得的生物学。我们的方法使用模型系统， 优先考虑和表征基因是创新的，将提供深入跟踪所需的关键见解- 在小鼠模型和临床研究中。一些鉴定的基因可能指向可用于治疗的靶点。 预防和治疗肥胖及其并发症，对一般人群有临床影响。

项目成果

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

肥胖症中巨噬细胞 PEPD 的失调决定了脂肪组织纤维炎症和胰岛素抵抗。

• DOI: 10.1038/s42255-022-00561-5
• 发表时间: 2022
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Pellegrinelli,V;Rodriguez-Cuenca,S;Rouault,C;Figueroa-Juarez,E;Schilbert,H;Virtue,S;Moreno-Navarrete,JM;Bidault,G;Vázquez-Borrego,MC;Dias,AR;Pucker,B;Dale,M;Campbell,M;Carobbio,S;Lin,YH;Vacca,M;Aron-Wisnewsky,J;Mora,
• 通讯作者: Mora,