scholarly journals Using Mendelian randomization to understand and develop treatments for neurodegenerative disease

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Catherine S Storm ◽  
Demis A Kia ◽  
Mona Almramhi ◽  
Nicholas W Wood
Keyword(s):  
Risk Factors ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Translational Medicine ◽  
Mendelian Randomization ◽  
Genetic Data ◽  
Molecular Pathways ◽  
Disease Research ◽  
The Impact

Abstract Common neurodegenerative diseases are thought to arise from a combination of environmental and genetic exposures. Mendelian randomization is a powerful way to leverage existing genetic data to investigate causal relationships between risk factors and disease. In recent years, Mendelian randomization has gathered considerable traction in neurodegenerative disease research, providing valuable insights into the aetiology of these conditions. This review aims to evaluate the impact of Mendelian randomization studies on translational medicine for neurodegenerative diseases, highlighting the advances made and challenges faced. We will first describe the fundamental principles and limitations of Mendelian randomization and then discuss the lessons from Mendelian randomization studies of environmental risk factors for neurodegeneration. We will illustrate how Mendelian randomization projects have used novel resources to study molecular pathways of neurodegenerative disease and discuss the emerging role of Mendelian randomization in drug development. Finally, we will conclude with our view of the future of Mendelian randomization in these conditions, underscoring unanswered questions in this field.

scholarly journals The impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bi-directional Mendelian randomization study

2020 ◽  
Author(s):  
SL Au Yeung ◽  
MC Borges ◽  
DA Lawlor ◽  
CM Schooling
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Lung Function ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Summary Statistics ◽  
The Impact ◽  
Genetic Instruments

AbstractBackgroundObservational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be susceptible to residual confounding. We conducted a 2 sample Mendelian randomization study using summary statistics from genome wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.MethodsWe obtained genetic instruments for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from publicly available UK Biobank summary statistics (n = 421,986). We applied these genetic instruments for FEV1 (260) and FVC (320) to publicly available GWAS summary statistics for coronary artery disease (CAD) (n = 184,305), stroke and its subtypes (n = 446,696), atrial fibrillation (n = 1,030,836), and heart failure (n = 977,320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, and multivariable Mendelian randomization. We also conducted bi-directional Mendelian randomization to assess whether CVD affects lung function.ResultsFEV1 and FVC were inversely associated with CAD (odds ratio (OR) per standard deviation (SD) increase, 0.72 (95% confidence interval (CI) 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (0.82 to 1.00)), ischemic stroke (0.87 (95%CI 0.77 to 0.99), 0.90 (95%CI 0.80 to 1.00)), small vessel stroke (0.78, (95%CI 0.61 to 1.00), 0.74 (95%CI 0.61 to 0.92)), and large artery stroke (0.69 (95%CI 0.54 to 0.89), 0.72 (95%CI 0.57 to 0.91)). FEV1 and FVC were inversely associated with type 2 diabetes (0.75 (95%CI 0.62 to 0.90), 0.67 (95%CI 0.58 to 0.79)) and systolic blood pressure. Sensitivity analyses produced similar direction for most outcomes although the magnitude sometimes differed. Adjusting for height attenuated results for CAD (e.g. OR for 1SD FEV1 0.95 (0.76 to 1.20), but this may reflect weak instrument bias. This adjustment did not attenuate effects for stroke or type 2 diabetes. No strong evidence was observed for CVD affecting lung function.ConclusionHigher lung function likely protect against CAD and stroke.

scholarly journals Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3460
Author(s):  
Larry N. Singh ◽  
Shih-Han Kao ◽  
Douglas C. Wallace
Keyword(s):  
Mitochondrial Dna ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Genetic Factors ◽  
Mitochondrial Genetics ◽  
Dna Variation ◽  
Parkinson’S Diseases ◽  
And Function ◽  
The Impact

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

Stress, Cortisol and Suicide Risk

2019 ◽  
Author(s):  
Daryl Brian O'Connor
Keyword(s):  
Risk Factors ◽  
Suicidal Behavior ◽  
Suicide Risk ◽  
Stressful Events ◽  
Additional Risk ◽  
Global Health Issue ◽  
History Of ◽  
Hpa Axis Activity ◽  
The Impact

Suicide is a global health issue accounting for at least 800,000 deaths per annum. Numerous models have been proposed that differ in their emphasis on the role of psychological, social, psychiatric and neurobiological factors in explaining suicide risk. Central to many models is a stress-diathesis component which states that suicidal behavior is the result of an interaction between acutely stressful events and a susceptibility to suicidal behavior (a diathesis). This article presents an overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide. Evidence for other putative stress-related suicide risk factors including childhood trauma, impaired executive function, impulsivity and disrupted sleep are considered together with the impact of family history of suicide, perinatal and epigenetic influences on suicide risk.

scholarly journals The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1700
Author(s):  
Melissa Chalada ◽  
Charmaine A. Ramlogan-Steel ◽  
Bijay P. Dhungel ◽  
Christopher J. Layton ◽  
Jason C. Steel
Keyword(s):  
Risk Factors ◽  
Ultraviolet Radiation ◽  
Uveal Melanoma ◽  
World Health Organisation ◽  
World Health ◽  
Genetic Mutations ◽  
High Incidence ◽  
The World ◽  
The Impact

Uveal melanoma (UM) is currently classified by the World Health Organisation as a melanoma caused by risk factors other than cumulative solar damage. However, factors relating to ultraviolet radiation (UVR) susceptibility such as light-coloured skin and eyes, propensity to burn, and proximity to the equator, frequently correlate with higher risk of UM. These risk factors echo those of the far more common cutaneous melanoma (CM), which is widely accepted to be caused by excessive UVR exposure, suggesting a role of UVR in the development and progression of a proportion of UM. Indeed, this could mean that countries, such as Australia, with high UVR exposure and the highest incidences of CM would represent a similarly high incidence of UM if UVR exposure is truly involved. Most cases of UM lack the typical genetic mutations that are related to UVR damage, although recent evidence in a small minority of cases has shown otherwise. This review therefore reassesses statistical, environmental, anatomical, and physiological evidence for and against the role of UVR in the aetiology of UM.

scholarly journals Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Uta Düesberg ◽  
Julia Wosniok ◽  
Lutz Naehrlich ◽  
Patience Eschenhagen ◽  
Carsten Schwarz
Keyword(s):  
Risk Factors ◽  
Cystic Fibrosis ◽  
Lung Function ◽  
Aspergillus Fumigatus ◽  
Age Groups ◽  
Antibiotic Use ◽  
Lower Lung ◽  
Lung Infections ◽  
The Impact

Abstract Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.

scholarly journals Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis

PLoS Medicine ◽  
2019 ◽  
Vol 16 (8) ◽  
pp. e1002893 ◽  
Author(s):  
James Yarmolinsky ◽  
Caroline L. Relton ◽  
Artitaya Lophatananon ◽  
Kenneth Muir ◽  
Usha Menon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Epithelial Ovarian Cancer ◽  
Mendelian Randomization ◽  
Ovarian Cancer Risk ◽  
Mendelian Randomization Analysis ◽  
Randomization Analysis

scholarly journals Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis

2018 ◽  
Vol 118 (02) ◽  
pp. 229-250 ◽  
Author(s):  
H. Spronk ◽  
T. Padro ◽  
J. Siland ◽  
J. Prochaska ◽  
J. Winters ◽  
...  
Keyword(s):  
Risk Factors ◽  
Antithrombotic Therapy ◽  
Thrombus Formation ◽  
Consensus Conference ◽  
Risk Scores ◽  
Dependent Manner ◽  
Metabolomics Data ◽  
Circulating Cells ◽  
The Impact

AbstractAtherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Mobile internet and consumer happiness: the role of risk

2018 ◽  
Vol 28 (3) ◽  
pp. 785-803 ◽  
Author(s):  
Ge Zhan ◽  
Zhimin Zhou
Keyword(s):  
Risk Factors ◽  
Online Survey ◽  
Well Being ◽  
Mobile Internet ◽  
Moderating Effects ◽  
Content Type ◽  
Frequency Of Use ◽  
The Impact ◽  
Or Applications

Purpose The purpose of this paper is to investigate the influence of mobile internet (MI) use and risk factors on MI happiness. Design/methodology/approach An online survey with 521 MI users was conducted to test the direct and moderating effects of risk factors on MI happiness. Findings The results provide evidence that there is a non-linear relationship between variety of use and MI happiness, and consumers become happier with increased frequency of use. The results also indicate that the privacy risk and task risk reduce MI happiness, and both types of risks moderate the inverted U-shaped relationship between variety of use and MI happiness. Research limitations/implications This study reconciles two opposing theories, stimulation vs displacement, on the impact of internet use on consumer well-being. The findings suggest that the stimulation effect of MI use is associated with an intermediate level of usage variety, while social displacement is more likely connected with higher- or lower-variety of use. Risk plays an important role in exploring the boundary conditions of both theories. The findings also have important implications to the debate over the role of privacy in consumer adoption of internet services or applications. Originality/value This study reconciles two opposing theories, stimulation vs displacement, on consumer happiness by elaborating the role of risk associated with MI use.

scholarly journals Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1351 ◽  
Author(s):  
Luca Rinaldi ◽  
Riccardo Nevola ◽  
Gianluigi Franci ◽  
Alessandro Perrella ◽  
Giusy Corvino ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Immune Surveillance ◽  
Liver Stiffness ◽  
Virologic Response ◽  
Direct Acting Antivirals ◽  
Direct Role ◽  
Direct Acting ◽  
The Impact

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.

scholarly journals The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 435 ◽  
Author(s):  
Anna Winiarska-Mieczan ◽  
Ewa Baranowska-Wójcik ◽  
Małgorzata Kwiecień ◽  
Eugeniusz R. Grela ◽  
Dominik Szwajgier ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Negative Impact ◽  
Functional Disorders ◽  
Brain Functions ◽  
Diet Supplements ◽  
The Impact ◽  
The Brain ◽  
All Diseases

Neurodegenerative diseases are progressive diseases of the nervous system that lead to neuron loss or functional disorders. Neurodegenerative diseases require long-term, sometimes life-long pharmacological treatment, which increases the risk of adverse effects and a negative impact of pharmaceuticals on the patients’ general condition. One of the main problems related to the treatment of this type of condition is the limited ability to deliver drugs to the brain due to their poor solubility, low bioavailability, and the effects of the blood-brain barrier. Given the above, one of the main objectives of contemporary scientific research focuses on the prevention of neurodegenerative diseases. As disorders related to the competence of the antioxidative system are a marker in all diseases of this type, the primary prophylactics should entail the use of exogenous antioxidants, particularly ones that can be used over extended periods, regardless of the patient’s age, and that are easily available, e.g., as part of a diet or as diet supplements. The paper analyzes the significance of the oxidoreductive balance in the pathogenesis of neurodegenerative diseases. Based on information published globally in the last 10 years, an analysis is also provided with regard to the impact of exogenous antioxidants on brain functions with respect to the prevention of this type of diseases.

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