An integrated genetic and proteomic approach to understanding cardiovascular disease aetiology

了解心血管疾病病因学的综合遗传和蛋白质组学方法

基本信息

  • 批准号:
    MR/S004068/1
  • 负责人:
  • 金额:
    $ 57.49万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2018
  • 资助国家:
    英国
  • 起止时间:
    2018 至 无数据
  • 项目状态:
    已结题

项目摘要

My research programme is focussed on using genomic technologies to understand the links between inflammation and cardiovascular disease. Despite advances in prevention and treatment, cardiovascular disease is the leading cause of death worldwide, highlighting the need for new therapeutic strategies. Most deaths are due to myocardial infarction or "heart attack". Heart attacks occur when fatty deposits in the wall of an artery rupture, triggering formation of a clot which blocks the blood supply to the heart. These fatty deposits build up over many years in a process called atherosclerosis. Traditionally atherosclerosis was thought to be solely due to build-up of excess fats, but over the last few decades the importance of inflammation in this process has been increasingly recognised. Inflammation usually occurs as a protective response to infection or injury, but in certain circumstances it can be harmful. A large number of drugs have been developed to treat harmful inflammation in autoimmune diseases such as rheumatoid arthritis. This raises the possibility that these or similar treatments could be effective in cardiovascular disease. Indeed, the recent CANTOS trial showed that canakinumab, a drug (originally designed for rheumatic diseases) which targets the IL1-beta protein, reduced coronary events in patients with high inflammation levels. There are multiple proteins involved in inflammation and so the challenge is identifying those that are the most promising drug targets.I propose to address this by integrating 'high-dimensional' genetic and proteomic data. As a result of advances in technology, it now possible to simultaneously measure large numbers of proteins (the 'proteome') in the blood in large numbers of individuals. However, simply showing an association of a protein with cardiovascular disease does not necessarily indicate that the protein is a valid drug target, as correlation does not always reflect causation. To circumvent this issue, I will integrate genetic information, utilising an approach called 'Mendelian randomisation'. This method takes advantage of the randomisation of genetic variants that occurs during reproduction, providing in effect a natural randomised trial. The first step is to identify genetic variants that affect the level of a particular protein. Then, by examining whether individuals who inherit such genetic variants are at higher or lower risk of cardiovascular disease, we can establish whether that protein is likely plays a causal role in disease and thus whether it is a valid drug target.In a complementary strand of work in collaboration with Prof. Justin Mason (Imperial College London), I am studying patients with Takayasu arteritis, a rare disease characterised by arterial inflammation, which often results in vascular narrowing, or, less commonly, dilatation (aneurysm). Cardiovascular complications are a major cause of morbidity. The prognosis in Takayasu arteritis is very variable - some patients have a benign course, while others develop progressive vascular injury. We will examine the plasma proteome to understand factors that influence this variability and to identify signatures that could be used to distinguish high-risk patients in need of stronger immunosuppressive treatment from those in whom milder, less toxic treatments would be sufficient. In addition, we anticipate that improved understanding of an extreme form of vascular inflammation should provide insights into cardiovascular disease more generally.
我的研究项目集中在使用基因组技术来了解炎症和心血管疾病之间的联系。尽管在预防和治疗方面取得了进展,但心血管疾病仍是全球死亡的主要原因,这突出表明需要新的治疗策略。大多数死亡是由于心肌梗塞或“心脏病发作”。当动脉壁中的脂肪沉积物破裂时,心脏病发作,引发血栓形成,阻塞心脏的血液供应。这些脂肪沉积物在称为动脉粥样硬化的过程中积累多年。传统上,动脉粥样硬化被认为仅仅是由于过量脂肪的积累,但在过去的几十年里,炎症在这一过程中的重要性越来越被认识到。炎症通常作为对感染或损伤的保护性反应而发生,但在某些情况下可能是有害的。已经开发了大量药物来治疗类风湿性关节炎等自身免疫性疾病中的有害炎症。这增加了这些或类似治疗对心血管疾病有效的可能性。事实上,最近的CANTOS试验表明,canakinumab,一种靶向IL 1-β蛋白的药物(最初设计用于风湿性疾病),减少了高炎症水平患者的冠状动脉事件。炎症涉及多种蛋白质,因此挑战在于识别那些最有希望的药物靶点。我建议通过整合“高维”遗传和蛋白质组数据来解决这个问题。由于技术的进步,现在可以同时测量大量个体血液中的大量蛋白质(“蛋白质组”)。然而,仅仅显示蛋白质与心血管疾病的关联并不一定表明该蛋白质是有效的药物靶点,因为相关性并不总是反映因果关系。为了解决这个问题,我将整合遗传信息,利用一种称为“孟德尔随机化”的方法。这种方法利用了在生殖过程中发生的遗传变异的随机化,实际上提供了一种自然的随机试验。第一步是确定影响特定蛋白质水平的遗传变异。然后,通过检查遗传这些遗传变异的个体患心血管疾病的风险是高还是低,我们可以确定该蛋白质是否可能在疾病中起因果作用,从而确定它是否是一个有效的药物靶点。(伦敦帝国理工学院伦敦),我正在研究高安动脉炎的患者,这是一种以动脉炎症为特征的罕见疾病,通常会导致血管狭窄,或者,较不常见的是,扩张(动脉瘤)。心血管并发症是发病的主要原因。大动脉炎的预后是非常多变的-一些患者有一个良性的过程,而其他发展进行性血管损伤。我们将检查血浆蛋白质组,以了解影响这种变异性的因素,并确定可用于区分需要更强免疫抑制治疗的高危患者与那些温和,毒性较小的治疗就足够了的患者的特征。此外,我们预计,对血管炎症的极端形式的更好理解应该更普遍地提供对心血管疾病的见解。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.
  • DOI:
    10.1038/s41467-023-40679-y
  • 发表时间:
    2023-08-18
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Akbari, Parsa;Vuckovic, Dragana;Stefanucci, Luca;Jiang, Tao;Kundu, Kousik;Kreuzhuber, Roman;Bao, Erik L.;Collins, Janine H.;Downes, Kate;Grassi, Luigi;Guerrero, Jose A.;Kaptoge, Stephen;Knight, Julian C.;Meacham, Stuart;Sambrook, Jennifer;Seyres, Denis;Stegle, Oliver;Verboon, Jeffrey M.;Walter, Klaudia;Watkins, Nicholas A.;Danesh, John;Roberts, David J.;Di Angelantonio, Emanuele;Sankaran, Vijay G.;Frontini, Mattia;Burgess, Stephen;Kuijpers, Taco;Peters, James E.;Butterworth, Adam S.;Ouwehand, Willem H.;Soranzo, Nicole;Astle, William J.
  • 通讯作者:
    Astle, William J.
ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: A Mendelian randomization study: ACE inhibition and ACE2 expression
ACE 抑制和心脏代谢危险因素、肺 ACE2 和 TMPRSS2 基因表达以及血浆 ACE2 水平:孟德尔随机研究:ACE 抑制和 ACE2 表达
  • DOI:
    10.17863/cam.59620
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Gill D
  • 通讯作者:
    Gill D
Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation
血脂和心血管疾病结果的遗传决定因素:广角孟德尔随机化研究
  • DOI:
    10.1101/668970
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Allara E
  • 通讯作者:
    Allara E
Supplementary Tables and Figures from ACE inhibition and cardiometabolic risk factors, lung
ACE 抑制和心脏代谢危险因素、肺的补充表格和数据
  • DOI:
    10.6084/m9.figshare.13227438
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Gill D
  • 通讯作者:
    Gill D
Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
  • DOI:
    10.1038/s42255-020-00287-2
  • 发表时间:
    2020-10
  • 期刊:
  • 影响因子:
    20.8
  • 作者:
    Folkersen L;Gustafsson S;Wang Q;Hansen DH;Hedman ÅK;Schork A;Page K;Zhernakova DV;Wu Y;Peters J;Eriksson N;Bergen SE;Boutin TS;Bretherick AD;Enroth S;Kalnapenkis A;Gådin JR;Suur BE;Chen Y;Matic L;Gale JD;Lee J;Zhang W;Quazi A;Ala-Korpela M;Choi SH;Claringbould A;Danesh J;Davey Smith G;de Masi F;Elmståhl S;Engström G;Fauman E;Fernandez C;Franke L;Franks PW;Giedraitis V;Haley C;Hamsten A;Ingason A;Johansson Å;Joshi PK;Lind L;Lindgren CM;Lubitz S;Palmer T;Macdonald-Dunlop E;Magnusson M;Melander O;Michaelsson K;Morris AP;Mägi R;Nagle MW;Nilsson PM;Nilsson J;Orho-Melander M;Polasek O;Prins B;Pålsson E;Qi T;Sjögren M;Sundström J;Surendran P;Võsa U;Werge T;Wernersson R;Westra HJ;Yang J;Zhernakova A;Ärnlöv J;Fu J;Smith JG;Esko T;Hayward C;Gyllensten U;Landen M;Siegbahn A;Wilson JF;Wallentin L;Butterworth AS;Holmes MV;Ingelsson E;Mälarstig A
  • 通讯作者:
    Mälarstig A
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James Peters其他文献

Carcinogenesis bioassay data system.
致癌生物测定数据系统。
Outcomes of Focused Ultrasound Thalamotomy in Tremor Syndromes
聚焦超声丘脑切除术治疗震颤综合征的结果
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    8.6
  • 作者:
    James Peters;Joel Maamary;K. Kyle;Nick Olsen;Lyndsey Jones;Samuel Bolitho;Yael Barnett;Ben Jonker;Stephen Tisch
  • 通讯作者:
    Stephen Tisch
Cerebellar atrophy with Chiari malformation: An example of trans-synaptic degeneration?
  • DOI:
    10.1016/j.jocn.2019.08.005
  • 发表时间:
    2019-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    James Peters;Catherine Ding;Shalini Amukotuwa;Peter Kempster
  • 通讯作者:
    Peter Kempster
Radiation Dose Reduction of Computed Tomography in Complex Distal Femur Fractures: A Cadaver Study to Develop a Low Dose Scanning Protocol
复杂股骨远端骨折中计算机断层扫描的辐射剂量减少:开发低剂量扫描协议的尸体研究
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nicholas O’Neill;Samuel J Wisniewski;Michael Adams;James Peters;Michael Wagner
  • 通讯作者:
    Michael Wagner
Numerical solutions for space–time conformable nonlinear partial differential equations via a scientific machine learning technique
通过一种科学机器学习技术求解时空适定性非线性偏微分方程的数值解
  • DOI:
    10.1016/j.neucom.2024.129134
  • 发表时间:
    2025-03-01
  • 期刊:
  • 影响因子:
    6.500
  • 作者:
    Hayman Thabet;Subhash Kendre;James Peters
  • 通讯作者:
    James Peters

James Peters的其他文献

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{{ truncateString('James Peters', 18)}}的其他基金

COVID-19: Longitudinal immunological and multi-omic profiling of haemodialysis patients
COVID-19:血液透析患者的纵向免疫学和多组学分析
  • 批准号:
    MR/V027638/1
  • 财政年份:
    2020
  • 资助金额:
    $ 57.49万
  • 项目类别:
    Research Grant
An integrated genetic and proteomic approach to understanding cardiovascular disease aetiology
了解心血管疾病病因学的综合遗传和蛋白质组学方法
  • 批准号:
    MR/S004068/2
  • 财政年份:
    2019
  • 资助金额:
    $ 57.49万
  • 项目类别:
    Fellowship
Research Initiation: Pulsed Spray Drop Sizing
研究启动:脉冲喷雾液滴尺寸
  • 批准号:
    8204437
  • 财政年份:
    1982
  • 资助金额:
    $ 57.49万
  • 项目类别:
    Standard Grant

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