Zhaoqing Wang

Bristol-Myers Squibb (United States)

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Dietmar Seiffert

Bristol-Myers Squibb (United States)

Julio A. Chirinos

University of Pennsylvania

Peter Schäfer

Bristol-Myers Squibb (United States)

Thomas P. Cappola

University of Pennsylvania

Jordana B. Cohen

University of Pennsylvania

Payman Zamani

University of Pennsylvania

Francisco Ramírez‐Valle

Bristol-Myers Squibb (United States)

Christina Ebert

Bristol-Myers Squibb (United States)

Oday Salman

University of Pennsylvania

Ali Javaheri

Washington University in St. Louis

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Bristol-Myers Squibb (United States)

170

Bristol-Myers Squibb (Germany)

University of Pennsylvania

Hospital of the University of Pennsylvania

Harvard University

Chinese Academy of Medical Sciences & Peking Union Medical College

British Heart Foundation

University of Edinburgh

Istituti di Ricovero e Cura a Carattere Scientifico

Capital Medical University

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Proteome-wide Mendelian randomization identifies candidate causal proteins for cardiovascular diseases

medRxiv (Cold Spring Harbor Laboratory) (2023)

Chen Li Nicolas Jay Supriya Sharma Katrina A. Catalano Emily Holzinger

Abstract Background Cardiovascular diseases (CVD) remain the leading cause of death worldwide, while a lack of clarity on underlying mechanisms has hindered development of novel therapies. Integration of human genetics and proteomics across different ancestries can provide novel, affordable, and systematic approach for target identification and prioritization. Methods Mendelian randomization approach was applied to unravel causal associations between 2,940 circulating proteins and 21 CVD. Genome-wide summary statistics from the largest genetic mapping of human plasma proteome and meta-analyses on CVD across FinnGen, UK Biobank and Biobank Japan were used. Forward and reverse causation were studied to distinguish respective targets and biomarkers. Genetic instruments for Europeans and East Asians were derived separately and applied to the cardiovascular outcomes in cohorts from corresponding ancestries. We further prioritized drug targets by integrating biological, clinical and population study evidence from cross-database annotations and literature review. Single-cell enrichment analysis and phenome-wide causality scan were performed to further understand target mechanism of action. Results We found 221 novel candidate causal proteins that impacted risk of one or more CVD through forward MR, and 16 biomarkers whose expression levels were affected by CVD through reverse MR (Bonferroni-adjusted P -value <= 0.05). Forward and reverse MR found largely non-overlapping proteins among CVD (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Many of the candidate causal proteins (73.4%) identified are supported by strong literature evidence for a role in immune response and atherosclerotic lesion formation, angiogenesis and vascular remodeling, myogenesis and cardiac progenitor cell differentiation, and energy metabolism. Single cell integration further prioritized ADAM23 for cardiomegaly, PAM for stable angina pectoris and ventricular arrythmia and LPL for peripheral artery disease, whose transcript expression were enriched in cardiomyocytes. Three protein functional groups were highlighted in the phenome-wide scan for their specific enrichment for CVD, including blood coagulation and fibrinolysis, angiogenesis and vascular remodeling, and cell proliferation and myogenesis. Conclusions Our study identified potential therapeutic targets for CVD and distinguished them from biomarkers due to reverse causation. This study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD.

Mendelian Randomization

Proteome

Genome-wide Association Study

10.1101/2023.10.16.23297103

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Citations (1)

Vitamin D levels and five cardiovascular diseases: A Mendelian randomization study

Heliyon (2023)

Zhishuai Zhang Shizheng Qiu Zhaoqing Wang Yang Hu

Cardiovascular disease is the leading cause of death worldwide, whilst vitamin D levels have been found to be associated with cardiovascular disease. To investigate the causal relationship between vitamin D levels and five cardiovascular diseases, a genome-wide association study (GWAS) was carried out using data on vitamin D levels (sample size = 79366), angina pectoris (18168 cases and 187840 controls), coronary heart disease (21012 cases and 197780 controls), lacunar stroke (6030 cases and 248929 controls), heart attack (10693 cases and 451187 controls), and hypertension (55917 cases and 162837 controls), with a Mendelian randomization (MR) analysis being subsequently performed. Six single nucleotide polymorphisms were used as instrumental variables (IVs). In addition, sensitivity analysis was performed to verify the reliability of the MR results here. The results showed a causal relationship between vitamin D levels and angina pectoris (OR = 0.51, 95 % CI: 0.28–0.93, P = 0.03), coronary heart disease (OR = 0.53, 95 % CI: 0.34–0.81, P = 0.004), and lacunar stroke (OR = 0.41, 95 % CI: 0.20–0.86, P = 0.02), but no causal relationship with heart attacks (OR = 1.00, 95 % CI: 0.99–1.01, P = 0.76) or hypertension (OR = 0.99, 95 % CI: 0.73–1.34, P = 0.94). Additionally, our IVs data showed no heterogeneity or pleiotropy, whilst the results of the MR analysis were reliable. This study contributes to the prevention and treatment of these five cardiovascular diseases.

Mendelian Randomization

Mendelian inheritance

10.1016/j.heliyon.2023.e23674

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An optimized agonist peptide of protease-activated receptor 4 and its use in a validated platelet-aggregation assay

Platelets (2022)

Jing Yang Claudio Mapelli Zhaoqing Wang Chi Shing Sum Ji Hua

Protease-activated receptor 4 (PAR4) is a promising drug target to improve the efficacy/safety window of antiplatelet agents. The native peptide GYPGQV and the more potent peptide AYPGKF, are PAR4-specific activators. However, these PAR4 agonist peptides (APs) elicit an agonist response, for example, platelet aggregation, at concentrations of 50 to 1000 µM in platelet-function assays, thereby limiting their utility to monitor the pharmacodynamic effects of PAR4 antagonists over a wide concentration range. Improved pharmacodynamic assays are needed for clinical development of PAR4 antagonists. We attempted to identify potent PAR4 APs to aid development of robust assays for optimization of PAR4 antagonists. Using an AYPG-based biased phage display peptide library approach followed by chemical peptide optimization, A-Phe(4-F)-PGWLVKNG was identified. This peptide demonstrated an EC50 value of 3.4 µM in a platelet-aggregation assay, which is 16-fold more potent than AYPGKF. Using this new PAR4 AP, a platelet-rich plasma-aggregation assay using light-transmission aggregometry was developed and validated in a series of precision and reproducibility tests. PAR4 antagonist responses to PAR4 AP A-Phe(4-F)-PGWLVKNG (12.5 µM to 100 µM) were subsequently evaluated in this assay in vitro and ex vivo in a human study using BMS-986120, a PAR4 antagonist that entered clinical studies.

Protease-activated receptor

10.1080/09537104.2022.2053091

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Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

Cell Metabolism (2016)

Todd G. Kirchgessner Paul G. Sleph Jacek Ostrowski John A. Lupisella Carol S. Ryan

Liver X receptor

Apolipoprotein E

Animal studies

10.1016/j.cmet.2016.07.016

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Citations (128)

Research progress on treatment and diagnosis of pelvic fractrure

China Medical Herald (2010)

Zhaoqing Wang

This paper analyzed,synthesized and generalized referred to relevance documents,and overviewed the diagno sis and clinical research,and provided some theoretical reference for accurate diagnosis and effective treatment of pelvic fracture.

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[Right cervical lymph node enlargement].

PubMed (2013)

Jian-lan Xie Xiaoge Zhou Zhaoqing Wang

1.病例简介:患者男,64岁.于2011年1月无意中发现右颈部包块,约黄豆大小.无压痛、盗汗、发热等不适.于当地医院行右侧颈部淋巴结针刺活检,病理诊断考虑为恶性淋巴瘤,建议切除活检明确诊断.患者于2011年3月8日取右颈部淋巴结(大小3.5 cmx2.0cm×0.8cm)活检,同时全身检查发现双颈、双腋下、双腹股沟淋巴结肿大,最大直径为4 cm,肝脾不大,当地医院诊断为非霍奇金淋巴瘤(弥漫性大B细胞淋巴瘤Ⅲa期),给予CTOD(环磷酰胺、吡柔比星、长春新碱、地塞米松)联合利妥昔单抗方案化疗.因8次规律性化疗结束,达到部分缓解,故于2012年7月来我院进一步诊断,经详细询问病史,患者既往无其他脏器肿瘤病史。

10.3760/cma.j.issn.0529-5807.2013.04.015

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Mitogen-activated Protein Kinase Phosphatase-1 Represses c-Jun NH2-terminal Kinase-mediated Apoptosis via NF-κB Regulation

Journal of Biological Chemistry (2008)

Zhaoqing Wang Ning Cao Danupon Nantajit Ming Fan Liu Y

The mechanism regulating radiation-induced anti-apoptotic response, a limiting factor in improving cell radiosensitivity, remains elusive. Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is the major member of MKPs that dephosphorylates and inactivates MAPK. Here we provide the evidence that MKP-1 was negatively bridging between NF-kappaB-mediated prosurvival pathway and c-Jun N-terminal kinase (JNK)-mediated proapoptotic response. MKP-1 was induced by gamma-radiation and repressed radiation-induced pro-apoptotic status. NF-kappaB RelA/p50 heterodimer was recruited to MKP-1 gene promoter to induce MKP-1 transcription. Deletion of the NF-kappaB-binding site or inactivation of NF-kappaB by its small interfering RNA significantly decreased the radiation-induced MKP-1 promoter activity. In addition, MKP-1-deficient mouse embryonic fibroblasts exhibited a prolonged activation of JNK but not p38 or extracellular signal-regulated kinase subfamilies of MAPKs. The prolonged activation of JNK was not induced by treatment with tumor necrosis factor alpha or interleukin-6, and inactivation of JNK but not p38 or ERK abolished radiation-induced proapoptotic status, indicating that JNK is specifically inhibited by radiation-induced MKP-1. Three MKP-1 wild type human tumor cell lines treated with MKP-1 small interfering RNA showed an increased proapoptotic response that can be rescued by overexpression of wild type mouse MKP-1. Together, these results suggest that MKP-1 is a NF-kappaB-mediated prosurvival effector in attenuating JNK-mediated pro-apoptotic response; NF-kappaB/MKP-1-mediated negative JNK regulation represents a potential therapeutic target for adjusting cell radiosensitivity.

ASK1

MAP2K7

c-Raf

Protein kinase R

Cyclin-dependent kinase 9

10.1074/jbc.m802229200

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Clinical and Proteomic Correlates of Plasma ACE2 (Angiotensin-Converting Enzyme 2) in Human Heart Failure

Hypertension (2020)

Julio A. Chirinos Jordana B. Cohen Lei Zhao Thomas C. Hanff Nancy K. Sweitzer

ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.

Angiotensin-converting enzyme 2

10.1161/hypertensionaha.120.15829

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Citations (45)

Endotrophin, a Collagen VI Formation–Derived Peptide, in Heart Failure

NEJM Evidence (2022)

Julio A. Chirinos Lei Zhao Alexander Lynge Reese‐Petersen Jordana B. Cohen Federica Genovese

Endotrophin, a collagen type VI-derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF).

10.1056/evidoa2200091

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Citations (33)

Proteomic Correlates And Prognostic Significance Of Kidney Injury In Heart Failure With Preserved Ejection Fraction

Journal of Cardiac Failure (2024)

Oday Salman Lei Zhao Jordana B. Cohen Marie‐Joe Dib Joe David Azzo

10.1016/j.cardfail.2023.10.235

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