Extensive Mendelian randomization study identifies potential causal risk factors for severe COVID-19

Abstract Background Identifying causal risk factors for severe coronavirus disease 2019 (COVID-19) is critical for its prevention and treatment. Many associated pre-existing conditions and biomarkers have been reported, but these observational associations suffer from confounding and reverse causation. Methods Here, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19. Results Our results highlight multiple body mass index (BMI)-related traits as risk-increasing: BMI (OR: 1.89, 95% CI: 1.51–2.37), hip circumference (OR: 1.46, 1.15–1.85), and waist circumference (OR: 1.82, 1.36–2.43). Our multivariable MR analysis further suggests that the BMI-related effect might be driven by fat mass (OR: 1.63, 1.03–2.58), but not fat-free mass (OR: 1.00, 0.61–1.66). Several white blood cell counts are negatively associated with severe COVID-19, including those of neutrophils (OR: 0.76, 0.61–0.94), granulocytes (OR: 0.75, 0.601–0.93), and myeloid white blood cells (OR: 0.77, 0.62–0.96). Furthermore, some circulating proteins are associated with an increased risk of (e.g., zinc-alpha-2-glycoprotein) or protection from severe COVID-19 (e.g., prostate-associated microseminoprotein). Conclusions Our study suggests that fat mass and white blood cells might be involved in the development of severe COVID-19. It also prioritizes potential risk and protective factors that might serve as drug targets and guide the effective protection of high-risk individuals.

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Prioritizing Causal Risk Factors for Severe COVID-19: An Exhaustive Mendelian Randomization Study

10.21203/rs.3.rs-149087/v1 ◽

2021 ◽

Cited By ~ 1

Author(s):

Yitang Sun ◽

Jingqi Zhou ◽

Kaixiong Ye

Keyword(s):

Risk Factors ◽

Fat Mass ◽

Blood Cells ◽

Drug Targets ◽

Large Scale ◽

Mendelian Randomization ◽

White Blood Cells ◽

Fat Free Mass ◽

Cell Counts ◽

Increased Risk

Abstract Identifying causal risk factors for severe coronavirus disease 2019 (COVID-19) is critical for its prevention and treatment. Many associated pre-existing conditions and biomarkers have been reported, but these observational associations suffer from confounding and reverse causation. Here, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19. Our results highlight multiple body mass index (BMI)-related traits as risk-increasing: BMI (OR:1.89, 95% CI:1.51–2.37), hip circumference (OR:1.46, 1.15–1.85), and waist circumference (OR:1.82, 1.36–2.43). Our multivariable MR analysis further shows that the BMI-related effect is driven by fat mass (OR:1.63, 1.03–2.58), but not fat-free mass (OR:1.00, 0.61–1.66). Several white blood cell counts are negatively associated with severe COVID-19, including those of neutrophils (OR:0.76, 0.61–0.94), granulocytes (OR:0.75, 0.601–0.93), and myeloid white blood cells (OR:0.77, 0.62–0.96). Furthermore, some circulating proteins are associated with an increased risk of (e.g., zinc-alpha-2-glycoprotein) or protection from severe COVID-19 (e.g., interleukin-3/6 receptor subunit alpha). Our study shows that fat mass and white blood cells underlie the etiology of severe COVID-19. It also identifies risk and protective factors that could serve as drug targets and guide the effective protection of high-risk individuals.

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The Clinical Characteristics and Risk Factors for Poor Prognosis Among HIV Patients with Talaromyces Marneffei Bloodstream Infection

10.21203/rs.3.rs-147633/v1 ◽

2021 ◽

Author(s):

Jianjun Sun ◽

Weiwei Sun ◽

Yang Tang ◽

Renfang Zhang ◽

Li Liu ◽

...

Keyword(s):

Risk Factors ◽

Blood Culture ◽

Bloodstream Infection ◽

Blood Cells ◽

Poor Prognosis ◽

Clinical Characteristics ◽

Aids Patients ◽

Talaromyces Marneffei ◽

Cell Counts ◽

Increased Risk

Abstract Background Talaromyces marneffei(TM) bloodstream infection is common in AIDS patients with extreme immunodeficiency in Southeast Asia and South China, however, clinical case study on TM bloodstream infection is scarce. We retrospectively analyze the clinical characteristics of TM bloodstream infection in hospitalized AIDS patients and determine the outcomes of hospitalization after diagnosis in our hospital over the past 5 years.Methods From January 2015 to July 2020, cases of TM detected by blood culture in patients admitted to our center were sorted and analyzed. The admission complaints, blood cells, biochemistry, CD4/CD8 count and 1,3-β-D-glucan, procalcitonin, CRP level on the day of blood culture test, and outcomes during hospitalization were analyzed. Logistic regression analysis was performed for the risk factors for poor prognosis. Spearman correlation analysis was used to analyze the correlation between peripheral blood cells, albumin and the time required for TM to become positive in blood culture. The difference was statistically significant when the P value was <0.05. Results A total of 87 patients were collected, with a median age of 34 years, a median hemoglobin of 94 g/L and CD4 count of 7/µl. The rate of TM bloodstream infection among all in-hospital patients increased from 0.99% in 2015 to 2.09% in 2020(half year). Patients with TM bloodstream infection with a CD8 count <200/µl had a 12.6-fold higher risk of poor prognosis than those with a CD8 count >200/µl (p=0.04), and those with 1,3-β-D-glucan <100 pg/mL had a 34.9-fold higher risk of poor prognosis than those with 1,3-beta-D-glucan >100 pg/mL (p=0.01).Conclusions TM bloodstream infection is becoming more common in advanced AIDS patients in endemic areas. For those patients with extremely low CD4 and CD8 cell counts below 200/µl, the 1,3-β-D-glucan <100 pg/mL are with an increased risk of poor prognosis.

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The Duffy-null genotype and risk of infection

Human Molecular Genetics ◽

10.1093/hmg/ddaa208 ◽

2020 ◽

Vol 29 (20) ◽

pp. 3341-3349

Author(s):

Sophie E Legge ◽

Rune H Christensen ◽

Liselotte Petersen ◽

Antonio F Pardiñas ◽

Matthew Bracher-Smith ◽

...

Keyword(s):

Blood Cells ◽

Middle Eastern ◽

African Ancestry ◽

Strong Association ◽

White Blood Cells ◽

Population Based ◽

Risk Of Infection ◽

Cell Counts ◽

Increased Risk ◽

The Uk

Abstract Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimize risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells, because of the Duffy-null (CC) genotype at rs2814778 in the ACKR1 gene. Here, we investigate whether the Duffy-null genotype is associated with the risk of infection using the UK Biobank sample and the iPSYCH Danish case-cohort study, two population-based samples from different countries and age ranges. We found that a high proportion of those with the Duffy-null genotype (21%) had a neutrophil count below the threshold often used as a cut-off for access to relevant treatments, compared with 1% of those with the TC/TT genotype. In addition we found that despite its strong association with lower average neutrophil counts, the Duffy-null genotype was not associated with an increased risk of infection, viral or bacterial. These results have widespread implications for the clinical treatment of individuals of African ancestry and indicate that neutrophil thresholds to access treatments could be lowered in individuals with the Duffy-null genotype without an increased risk of infection.

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White Blood Cells and Severe COVID-19: A Mendelian Randomization Study

Journal of Personalized Medicine ◽

10.3390/jpm11030195 ◽

2021 ◽

Vol 11 (3) ◽

pp. 195

Author(s):

Yitang Sun ◽

Jingqi Zhou ◽

Kaixiong Ye

Keyword(s):

Blood Cell ◽

Cell Count ◽

White Blood Cell Count ◽

White Blood Cell ◽

Blood Cells ◽

Mendelian Randomization ◽

Association Studies ◽

White Blood Cells ◽

Genome Wide Association Studies ◽

Blood Cell Count

Increasing evidence shows that white blood cells are associated with the risk of coronavirus disease 2019 (COVID-19), but the direction and causality of this association are not clear. To evaluate the causal associations between various white blood cell traits and the COVID-19 susceptibility and severity, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses with summary statistics from the largest and most recent genome-wide association studies. Our MR results indicated causal protective effects of higher basophil count, basophil percentage of white blood cells, and myeloid white blood cell count on severe COVID-19, with odds ratios (OR) per standard deviation increment of 0.75 (95% CI: 0.60–0.95), 0.70 (95% CI: 0.54–0.92), and 0.85 (95% CI: 0.73–0.98), respectively. Neither COVID-19 severity nor susceptibility was associated with white blood cell traits in our reverse MR results. Genetically predicted high basophil count, basophil percentage of white blood cells, and myeloid white blood cell count are associated with a lower risk of developing severe COVID-19. Individuals with a lower genetic capacity for basophils are likely at risk, while enhancing the production of basophils may be an effective therapeutic strategy.

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Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study

Acta Endocrinologica ◽

10.1530/eje.1.02065 ◽

2006 ◽

Vol 154 (1) ◽

pp. 131-139 ◽

Cited By ~ 18

Author(s):

Lenora M Camarate S M Leão ◽

Mônica Peres C Duarte ◽

Dalva Margareth B Silva ◽

Paulo Roberto V Bahia ◽

Cláudia Medina Coeli ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Postmenopausal Women ◽

Fat Mass ◽

Visceral Fat ◽

Increased Risk

Background: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. Objective: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. Design: Thirty-seven postmenopausal women aged 42–62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. Methods: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. Results: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. Conclusion: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.

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Body composition in childhood: effects of normal growth and disease

Proceedings of The Nutrition Society ◽

10.1079/pns2003261 ◽

2003 ◽

Vol 62 (2) ◽

pp. 521-528 ◽

Cited By ~ 38

Author(s):

J. C. K. Wells

Keyword(s):

Body Composition ◽

Childhood Obesity ◽

Fat Mass ◽

Lean Mass ◽

Normal Weight ◽

Fat Free Mass ◽

General Interest ◽

Childhood And Adolescence ◽

Adult Disease ◽

Increased Risk

Body composition in children is of increasing interest within the contexts of childhood obesity, clinical management of patients and nutritional programming as a pathway to adult disease. Energy imbalance appears to be common in many disease states; however, body composition is not routinely measured in patients. Traditionally, clinical interest has focused on growth or nutritional status, whereas more recent studies have quantified fat mass and lean mass. The human body changes in proportions and chemical composition during childhood and adolescence. Most of the weight gain comprises lean mass rather than fat. In general, interest has focused on percentage fat, and less attention has been paid to the way in which lean mass varies within and between individuals. In the general population secular trends in BMI have been widely reported, indicating increasing levels of childhood obesity, which have been linked to reduced physical activity. However, lower activity levels may potentially lead not only to increased fatness, but also to reduced lean mass. This issue merits further investigation. Diseases have multiple effects on body composition and may influence fat-free mass and/or fat mass. In some diseases both components change in the same direction, whereas in other diseases, the changes are contradictory and may be concealed by relatively normal weight. Improved techniques are required for clinical evaluations. Both higher fatness and reduced lean mass may represent pathways to an increased risk of adult disease.

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Potential effects on cardiometabolic risk factors and body composition by short message service (SMS)-guided training after recent minor stroke or transient ischaemic attack: post hoc analyses of the STROKEWALK randomised controlled trial

BMJ Open ◽

10.1136/bmjopen-2021-054851 ◽

2021 ◽

Vol 11 (10) ◽

pp. e054851

Author(s):

Birgit Maria Vahlberg ◽

Erik Lundström ◽

Staffan Eriksson ◽

Ulf Holmback ◽

Tommy Cederholm

Keyword(s):

Risk Factors ◽

Body Composition ◽

Mobile Phone ◽

Fat Mass ◽

Text Messaging ◽

Standard Care ◽

Cardiometabolic Risk ◽

Fat Free Mass ◽

Control Group ◽

Randomised Controlled

ObjectivesTo evaluate effects of mobile phone text-messaging exercise instructions on body composition, cardiometabolic risk markers and self-reported health at 3 months after stroke.DesignRandomised controlled intervention study with per-protocol analyses.SettingUniversity Hospital in Sweden.ParticipantsSeventy-nine patients (mean (SD) age 64 (10) years, 37% female) ≥18 years with good motor function (modified Rankin Scale ≤2) and capable to perform 6 min walking test at hospital discharge were randomised to either intervention (n=40) or control group (n=39). Key exclusion criteria: subarachnoid bleeding, uncontrolled hypertension, severe psychiatric problems or cognitive limitations.InterventionsThe intervention group received beyond standard care, daily mobile phone instructional text messages to perform regular outdoor walking and functional leg exercises. The control group received standard care.Main outcome measuresFat mass and fat-free mass were estimated by bioelectric impedance analysis. Cardiometabolic risk factors like blood lipids, glycated haemoglobin and blood glucose were analysed at baseline and after 3 months.ResultsBoth groups changed favourably in fat-free mass (1.83 kg, 95% CI 0.77 to 2.89; p=0.01, effect size (ES)=0.63 vs 1.22 kg, 95% CI 0.39 to 2.0; p=0.05, ES=0.54) and fat mass (−1.30 kg, 95% CI −2.45 to −0.14; p=0.029, ES=0.41 vs −0.76 kg, 95% CI −1.74 to 0.22; p=0.123, ES=0.28). Also, many cholesterol related biomarkers improved; for example, total cholesterol −0.65 mmol/L, 95% CI −1.10 to −0.2; p=0.06, ES: 0.5 vs −1.1 mmol/L, 95% CI −1.47 to −0.56; p>0.001, ES=0.8. However, there were no between-group differences. At 3 months, 94% and 86%, respectively, reported very good/fairly good health in the text messaging and control groups.ConclusionsNo clear effect of 3 months daily mobile phone delivered training instructions was detected on body composition, cardiovascular biochemical risk factors or self-perceived health. Further research is needed to evaluate secondary prevention efforts in larger populations after recent stroke.Trial registration numberNCT02902367.

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Evaluating the effects of alcohol and tobacco use on cardiovascular disease using multivariable Mendelian randomization

10.1101/757146 ◽

2019 ◽

Cited By ~ 1

Author(s):

Daniel B. Rosoff ◽

George Davey Smith ◽

Nehal Mehta ◽

Toni-Kim Clarke ◽

Falk W. Lohoff

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Alcohol Use ◽

Tobacco Use ◽

Mendelian Randomization ◽

Association Studies ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Cvd Risk ◽

Increased Risk

ABSTRACTAlcohol and tobacco use, two major modifiable risk factors for cardiovascular disease (CVD), are often consumed together. Using large publicly available genome-wide association studies (results from > 940,000 participants), we conducted two-sample multivariable Mendelian randomization (MR) to simultaneously assess the independent effects of alcohol and tobacco use on CVD risk factors and events. We found genetic instruments associated with increased alcohol use, controlling for tobacco use, associated with increased high-density-lipoprotein-cholesterol (HDL-C), decreased triglycerides, but not with coronary heart disease (CHD), myocardial infarction (MI), nor stroke; and instruments for increased tobacco use, controlling for alcohol use, associated with decreased HDL-C, increased triglycerides, and increased risk of CHD and MI. Exploratory analysis found associations with HDL-C, LDL-C, and intermediate-density-lipoprotein metabolites. Consistency of results across complementary methods accommodating different MR assumptions strengthened causal inference, providing strong genetic evidence for the causal effects of modifiable lifestyle risk factors on CVD risk.

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Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes

Wellcome Open Research ◽

10.12688/wellcomeopenres.15334.2 ◽

2019 ◽

Vol 4 ◽

pp. 113 ◽

Cited By ~ 12

Author(s):

Venexia M Walker ◽

Neil M Davies ◽

Gibran Hemani ◽

Jie Zheng ◽

Philip C Haycock ◽

...

Keyword(s):

Risk Factors ◽

Web Application ◽

Drug Targets ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

R Package ◽

Sensitivity Analyses ◽

Link Type ◽

Study Results

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

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ALLIUM SATIVUM ESSENTIAL OIL (ASEO);

The Professional Medical Journal ◽

10.29309/tpmj/2017.24.04.1519 ◽

2017 ◽

Vol 24 (04) ◽

pp. 612-616

Author(s):

Faisal Irshad ◽

Hina Mawani ◽

Sana Naz

Keyword(s):

Essential Oil ◽

Blood Cell ◽

Blood Cells ◽

Allium Sativum ◽

White Blood Cells ◽

Albino Rats ◽

Serum Triglycerides ◽

Cell Counts ◽

Blood Cell Counts ◽

Animal House

Objectives: To determine the effects of Allium sativum essential oil (ASEO)phytotherapy on serum triglycerides, total cholesterol, HDLc, LDLc and blood cell counts inalbino rat model. Study design: Experimental study. Setting and Duration: Animal House,Sindh Agriculture University and Isra University Hyderabad from May 2014 to January 2015.Materials and Methods: 60 albino rats were divided into four groups. Controls were givenPlacebo. Experimental rat groups were given ASEO 100 mg/kg, 200 mg/kg and 300 mg/kgorally for 30 days. Cardiac puncture was performed for blood sampling. Research variableswere analyzed on Statistix 10.0 (USA). Results: Blood lipids showed significant reduction invarious blood lipid fractions. Serum LDLc exhibited with a concomitant rise in serum HDLc (p=0.0001) in high ASEO treated rats. Red blood cells, white blood cells and platelet showedsignificant improvement ASEO fed rats (p=0.001). Conclusion: Allium sativum essential oil(ASEO) phytotherapy showed a rise in HDLc and a reduction in LDLc, triglycerides and totalcholesterol with improvement in red blood cell counts.

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