Using Mendelian Randomization Studies to Assess Causality and Identify New Therapeutic Targets in Cardiovascular Medicine

Zhao, Wei; Lee, Jung‐Jin; Rasheed, Awais; Saleheen, Danish

doi:10.1007/s40142-016-0103-4

Cited by 4 publications

(5 citation statements)

References 36 publications

(52 reference statements)

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“…Six proteins were implicated by MR analyses as nominally causal for CHD (Supplementary Data 15 ). LPA, which interferes with the fibrinolytic cascade 28 , has been previously demonstrated to be causal for CHD 29 , and served as a positive control. BCHE has previously been reported to be inversely associated with long-term CVD mortality 30 , and several polymorphisms within BCHE have been reported 31 to be associated with CHD risk factors.…”

Section: Resultsmentioning

confidence: 99%

Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

et al. 2018

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Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

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Section: Resultsmentioning

confidence: 99%

Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

et al. 2018

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“…Nicotine can induce the production of various inflammatory factors, including tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), nuclear factor‐kβ (NF‐kB), and C‐reactive protein (CRP; Lau et al, ; Y. Wang et al, ; Zingg et al, ), and is therefore implicated in the development of atherosclerosis. CRP, an extensively studied inflammatory factor, plays a main role in the development of atherosclerosis (Zhao, Lee, Rasheed, & Saleheen, ) and is used to predict the risk of coronary events (X. Zhang et al, ). CRP can also lead to the accumulation of low‐density lipoprotein (LDL) in the vascular wall and affect phagocytosis of LDL by macrophages (Shahriary, Panahi, Shirali, & Rahmani, ; Song et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Wang et al, 2004;Zingg et al, 2016), and is therefore implicated in the development of atherosclerosis. CRP, an extensively studied inflammatory factor, plays a main role in the development of atherosclerosis (Zhao, Lee, Rasheed, & Saleheen, 2016) and is used to predict the risk of coronary events (X. . CRP can also lead to the accumulation of low-density lipoprotein (LDL) in the vascular wall and affect phagocytosis of LDL by macrophages (Shahriary, Panahi, Shirali, & Rahmani, 2017;Song et al, 2017).…”

mentioning

confidence: 99%

Rosmarinic acid inhibits nicotine‐induced C‐reactive protein generation by inhibiting NLRP3 inflammasome activation in smooth muscle cells

Yao

Mao

et al. 2018

Journal Cellular Physiology

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Atherosclerosis is widely known to be a chronic inflammatory disease. C-reactive protein (CRP), an important inflammatory factor, plays an essential role in the pathogenesis of atherosclerosis. Nicotine, the main addictive component of cigarette, has been shown to induce the production of CRP. The aim of this study was to investigate the effect of rosmarinic acid (RA), a polyphenol with antiinflammatory activity, on nicotine-induced elevation of CRP in vascular smooth muscle cells (VSMCs). We found that pretreatment of VSMCs with RA attenuated nicotine-induced expression of CRP in a time- and dose-dependant manner. In addition, RA also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and reactive oxygen species (ROS) production resulting from nicotine treatment in VSMCs. To confirm these findings in vivo, we constructed a nicotine-induced atherosclerosis rat model. RA did not significantly reduce the serum nicotine level of the rats, whereas it significantly decreased the levels of serum lipids, including concentrations of cholesterol, triglycerides, and low-density lipoprotein cholesterol, and the serum level of CRP. RA also led to diminished nicotine-induced activation of NLRP3 inflammasome and elevation in the CRP level in the aortic tissue of the model rats. The results of this study suggested a protective role of RA in nicotine-induced atherosclerosis by inhibiting the ROS-NLRP3 inflammasome-CRP axial, and RA therefore represented a potential effective therapeutic approach to atherosclerosis, in particular for those who smoke.

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“…22 This approach provides unbiased causal estimates and overcomes observational study limitations such as confounding and reverse causality. 23…”

Section: Tablementioning

confidence: 99%

Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration

von Känel

2024

Semin Thromb Hemost

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By integrating findings from comprehensive reviews, meta-analyses, and cutting-edge genetic studies, this article illuminates the significance of stress-induced hypercoagulability in clinical medicine. In particular, the findings from numerous prospective cohort studies indicate that stress and hemostatic factors of a hypercoagulable state are associated with increased incident risk and poor prognosis for atherosclerotic cardiovascular disease and venous thromboembolism. Mendelian randomization studies suggest that these associations are partially causal. The review synthesizes extensive research on the link between acute and chronic stress and hypercoagulability, outlining a potential pathway from stress to thrombosis risk. Consistent with the allostatic load concept, acute stress-induced hypercoagulability, initially adaptive, can turn maladaptive under chronic stress or excessive acute stress, leading to arterial or venous thrombotic events. Individuals with predisposing factors, including atherosclerosis, thrombophilia, or immobilization, may exhibit an increased risk of thrombotic disease during stress. Contextual sociodemographic characteristics, the stress experience, and coping resources additionally modulate the extent of stress-induced hypercoagulability. Research into the neuroendocrine, cellular, and molecular bases reveals how stress influences platelet activation coagulation and fibrinolysis. The activation of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis, along with vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are the central mechanisms involved. Hemoconcentration, inflammation, endothelial dysfunction, and thrombopoiesis additionally contribute to stress-induced hypercoagulability. Further research is needed to prove a causal link between chronic stress and hypercoagulability. This includes exploring its implications for the prevention and management of thrombotic diseases in stressed individuals, with a focus on developing effective psychosocial and pharmacological interventions.

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Using Mendelian Randomization Studies to Assess Causality and Identify New Therapeutic Targets in Cardiovascular Medicine

Cited by 4 publications

References 36 publications

Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Rosmarinic acid inhibits nicotine‐induced C‐reactive protein generation by inhibiting NLRP3 inflammasome activation in smooth muscle cells

Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration

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