Total plasma and IgG glycomes, statin therapy and ASCVD events

总血浆和 IgG 糖组、他汀类药物治疗和 ASCVD 事件

• 批准号: 10464886
• 负责人: SAMIA MORA
• 金额: $ 44.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464886
• 关键词: Anti-Inflammatory Agents; Atherosclerosis; Award; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Blood Circulation; Blood Vessels; Blood specimen; Cardiovascular system; Case-Control Studies; Chronic; Clinical; Data; Development; Disease; Dose; Equilibrium; Evaluation; Event; Funding; Future; G-substrate; Genes; Glycobiology; Goals; Guidelines; Heterogeneity; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Immunoglobulin G; Immunoglobulins; Individual; Inflammation; Inflammatory; Innate Immune System; Intervention; Intervention Trial; Laboratory Research; Lipids; Measurement; Measures; Medicine; Molecular Epidemiology; Nested Case-Control Study; Pathologic Processes; Patients; Pattern; Phenotype; Physiological Processes; Placebos; Plasma; Plasma Proteins; Play; Polysaccharides; Post-Translational Protein Processing; Prevention; Primary Prevention; Process; Protein Glycosylation; Proteins; Proteomics; Randomized; Regimen; Research Design; Research Infrastructure; Risk; Risk Factors; Role; Secondary Prevention; Structure; Technology; Therapeutic; Tissues; Variant; atorvastatin; base; blood group; cardiovascular disorder risk; case control; chronic inflammatory disease; clinically relevant; cost effective; design; experience; glycosylation; innovation; insight; interest; multidisciplinary; new therapeutic target; novel; phenotypic data; prospective; protein function; response; rosuvastatin; sugar; targeted biomarker; targeted treatment; therapeutic target; vascular risk factor

7. Project Summary/Abstract Glycans are sugars attached to proteins in the enzymatic process of post-translational glycosylation. This post-translational modification of proteins enhances their functional heterogeneity and is important for many biological processes. Glycans play specific regulatory roles in modulating inflammation, the innate immune system, and other key physiological and pathological processes that are known to promote atherosclerosis. Most proteins are glycosylated, including inflammatory proteins and immunoglobulin G, the most abundant immunoglobulin in circulation. These and other circulating glycosylated proteins form the plasma glycome. Yet functional understanding of the role of glycosylation in ASCVD development and therapeutics has only recently emerged. Glycomics and glycosciences have lagged behind proteomics and other “omics”, in particular for cardiovascular applications where there is a deficiency in understanding the integral role that glycans play in atherosclerosis. However, recent advances in high-throughput glycomics technologies now allow the accurate identification and quantification of distinct glycans on circulating proteins in human plasma. In this competing R01 renewal, we propose to leverage the study design set up in the first funding period, using two nested case-control studies with deeply phenotyped vascular, lipid, and inflammatory biomarkers, to comprehensively evaluate the total plasma and immunoglobulin G glycomes in relation to ASCVD risk. The goal of this study is to advance our understanding of the human glycome by identifying glycosylation patterns related positively or inversely to incident ASCVD and risk factors, in particular inflammatory and vascular risk factors. Furthermore, new cardiovascular therapies targeting protein glycosylation or inflammation will be added on top of statin therapy, yet studies evaluating the impact of statins on protein glycosylation are scarce. To elucidate these important questions, we will conduct two prospective case- control studies (1,050 matched case-control pairs) leveraging the availability in both studies of baseline and year 1 blood samples for repeat measurements of glycans and vascular risk factors. The proposed study will evaluate a comprehensive panel of pro- and anti-inflammatory glycans isolated from both total plasma proteins and immunoglobulin G, examined in relation to vascular biomarkers, risk factors, and clinical events, as well as assess how statins modulate the balance of glycans. The proposed study will be accomplished in a cost- effective and efficient design because of the availability of the extensive phenotypic data from the award’s first cycle. This comprehensive approach utilizing recent advances in glycomics technologies to elucidate specific pro-and anti-inflammatory glycans has the potential to advance the field and develop innovative glycan-based targeted biomarkers or potential therapeutic approaches in line with precision cardiovascular medicine.

7. 项目总结/摘要 聚糖是在翻译后糖基化的酶促过程中附着在蛋白质上的糖。这 蛋白质的翻译后修饰增强了其功能异质性，对于许多人来说很重要 生物过程。聚糖在调节炎症、先天免疫中发挥特定的调节作用 系统以及已知促进动脉粥样硬化的其他关键生理和病理过程。 大多数蛋白质都是糖基化的，包括炎症蛋白和免疫球蛋白 G（最丰富的蛋白质） 循环中的免疫球蛋白。这些和其他循环糖基化蛋白形成血浆糖组。然而 对糖基化在 ASCVD 发展和治疗中的作用的功能性理解仅 最近出现的。糖组学和糖科学落后于蛋白质组学和其他“组学”， 特别是对于心血管应用，缺乏对心血管应用的整体作用的理解 聚糖在动脉粥样硬化中发挥作用。然而，高通量糖组学技术的最新进展 允许准确识别和定量人血浆中循环蛋白上的不同聚糖。 在这次竞争性的 R01 更新中，我们建议利用第一个资助期建立的研究设计， 使用两项具有深度表型血管、脂质和炎症生物标志物的巢式病例对照研究， 全面评估血浆总糖和免疫球蛋白 G 糖组与 ASCVD 风险的关系。这 这项研究的目标是通过鉴定糖基化来增进我们对人类糖组的理解 与 ASCVD 事件和危险因素（特别是炎症）呈正相关或负相关的模式 和血管危险因素。此外，针对蛋白质糖基化或 他汀类药物治疗将增加炎症治疗，但有研究评估他汀类药物对蛋白质的影响 糖基化很少。为了阐明这些重要问题，我们将进行两个前瞻性案例—— 对照研究（1,050 个匹配的病例对照对）利用基线研究和对照研究中的可用性 第一年的血液样本用于重复测量聚糖和血管危险因素。拟议的研究将 评估从血浆总蛋白中分离出的一组全面的促炎和抗炎聚糖 和免疫球蛋白 G，检查与血管生物标志物、危险因素和临床事件以及 评估他汀类药物如何调节聚糖的平衡。拟议的研究将在成本内完成 由于可以获得该奖项第一届的广泛表型数据，因此设计有效且高效 循环。这种综合方法利用糖组学技术的最新进展来阐明特定的 促炎和抗炎聚糖有潜力推进该领域并开发基于聚糖的创新 符合精准心血管医学的靶向生物标志物或潜在治疗方法。

项目成果

High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy.

• DOI: 10.1161/circulationaha.113.002671
• 发表时间: 2013-09-10
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Mora S;Glynn RJ;Ridker PM
• 通讯作者: Ridker PM

Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).

• DOI: 10.1161/circulationaha.113.004406
• 发表时间: 2014-02-11
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Khera AV;Everett BM;Caulfield MP;Hantash FM;Wohlgemuth J;Ridker PM;Mora S
• 通讯作者: Mora S

Partitioning the Genetic Architecture of Plasma Lipoprotein(a) and Kringle IV Type 2 Repeats: Implications for Therapeutic Lowering.

血浆脂蛋白 (a) 和 Kringle IV 2 型重复的遗传结构的划分：对治疗性降低的影响。

• DOI: 10.1373/clinchem.2017.280172
• 发表时间: 2017
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: Lawler,PatrickR;Mora,Samia
• 通讯作者: Mora,Samia

Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.

• DOI: 10.1016/j.jacc.2014.02.615
• 发表时间: 2014-08-05
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Boekholdt, S. Matthijs;Hovingh, G. Kees;Mora, Samia;Arsenault, Benoit J.;Amarenco, Pierre;Pedersen, Terje R.;LaRosa, John C.;Waters, David D.;DeMicco, David A.;Simes, R. John;Keech, Antony C.;Colquhoun, David;Hitman, Graham A.;Betteridge, John;Clearfield, Michael B.;Downs, John R.;Colhoun, Helen M.;Gotto, Antonio M., Jr.;Ridker, Paul M.;Grundy, Scott M.;Kastelein, John J. P.
• 通讯作者: Kastelein, John J. P.

Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.

• DOI: 10.1161/circulationaha.113.002670
• 发表时间: 2013-10-01
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Boekholdt SM;Arsenault BJ;Hovingh GK;Mora S;Pedersen TR;Larosa JC;Welch KM;Amarenco P;Demicco DA;Tonkin AM;Sullivan DR;Kirby A;Colhoun HM;Hitman GA;Betteridge DJ;Durrington PN;Clearfield MB;Downs JR;Gotto AM Jr;Ridker PM;Kastelein JJ
• 通讯作者: Kastelein JJ