scholarly journals The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study

2019 ◽  
Vol 110 (3) ◽  
pp. 685-690 ◽  
Author(s):  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Linoleic Acid ◽  
Blood Cell ◽  
White Blood Cell ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

ABSTRACT Background Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n–6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials. Objectives To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma. Methods We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)–control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality. Results Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (−0.03; 95% CI: −0.061, −0.004) and lower neutrophil count (−0.04; 95% CI: −0.057, −0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses. Conclusions LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

scholarly journals Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study

2020 ◽  
Vol 105 (7) ◽  
pp. e2398-e2407
Author(s):  
Jonathan Mark Fussey ◽  
Robin N Beaumont ◽  
Andrew R Wood ◽  
Bijay Vaidya ◽  
Joel Smith ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Thyroid Cancer ◽  
Thyroid Disease ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

Abstract Background The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. Methods We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. Results Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). Conclusions Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

scholarly journals Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank

2020 ◽  
Vol 9 (14) ◽  
Author(s):  
Shan Luo ◽  
Shiu Lun Au Yeung ◽  
Verena Zuber ◽  
Stephen Burgess ◽  
Catherine Mary Schooling
Keyword(s):  
Venous Thromboembolism ◽  
General Population ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Uk Biobank ◽  
Increased Risk ◽  
The Uk

Background Red blood cell (RBC) transfusion and erythropoiesis‐stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome‐wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best‐fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance–weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05–1.41) with VTE. Sensitivity analyses (mendelian randomization–Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

scholarly journals Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2218
Author(s):  
Shuai Yuan ◽  
Paul Carter ◽  
Amy M. Mason ◽  
Stephen Burgess ◽  
Susanna C. Larsson
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Intracerebral Hemorrhage ◽  
Genetic Variants ◽  
Odds Ratio ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Uk Biobank ◽  
The Uk

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

scholarly journals Author response: Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank

2020 ◽  
Author(s):  
Paul Carter ◽  
Mathew Vithayathil ◽  
Siddhartha Kar ◽  
Rahul Potluri ◽  
Amy M Mason ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Author Response ◽  
Uk Biobank ◽  
The Uk

scholarly journals Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

2021 ◽  
Vol 7 ◽  
Author(s):  
Shucheng Si ◽  
Jiqing Li ◽  
Yunxia Li ◽  
Wenchao Li ◽  
Xiaolu Chen ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Heart Diseases ◽  
Cerebrovascular Diseases ◽  
European Ancestry ◽  
Uk Biobank ◽  
Tyg Index ◽  
Metabolic Outcomes ◽  
Meta Regression ◽  
The Uk

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

scholarly journals White Blood Cell Count and Risk of Incident Lung Cancer in the UK Biobank

2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Jason Y Y Wong ◽  
Bryan A Bassig ◽  
Erikka Loftfield ◽  
Wei Hu ◽  
Neal D Freedman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Risk ◽  
Blood Cell ◽  
White Blood Cell ◽  
Lung Cancer Risk ◽  
Uk Biobank ◽  
Former Smokers ◽  
Never Smokers ◽  
The Uk ◽  
Incident Cases

Abstract Background The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK). Methods We evaluated 424 407 adults aged 37–73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006–2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference. Results There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HRQ4 = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers (ncases / n = 244 / 19 464, HRQ4 = 2.15, 95% CI = 1.46 to 3.16), former smokers (ncases / n = 280 / 69 198, HRQ4 = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (ncases / n = 108 / 111 294, HRQ4 = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (ncase s / n = 329 / 22 934, HRQ4 = 2.95, 95% CI = 2.04 to 4.26) and former smokers (ncases / n = 358/71 616, HRQ4 = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions. Conclusions Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men.

scholarly journals A Mendelian randomization study of telomere length and blood-cell traits

2020 ◽  
Author(s):  
Charleen D. Adams ◽  
Brian B. Boutwell
Keyword(s):  
Blood Cell ◽  
Telomere Length ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Mean Corpuscular Hemoglobin ◽  
Corpuscular Hemoglobin ◽  
Standard Deviation Increase ◽  
Mean Cell Volume ◽  
Distribution Width

AbstractWhether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n=9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n∼173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell (RBC) and white blood cell (WBC) counts, decreased mean corpuscular hemoglobin (MCH) and mean cell volume (MCV), and had no observable impact on mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to how germline mutations in TERT can lead to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.

scholarly journals Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank

2019 ◽  
Author(s):  
Huanwei Wang ◽  
Futao Zhang ◽  
Jian Zeng ◽  
Yang Wu ◽  
Kathryn E. Kemper ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Genetic Variants ◽  
Phenotypic Variability ◽  
Environmental Data ◽  
European Ancestry ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Genotype By Environment ◽  
A Genome ◽  
The Uk

AbstractGenotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank, and identified 75 significant vQTLs with P<2.0×10−9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.

The Role of Morning Plasma Cortisol in Obesity: A Bi-directional Mendelian Randomization Study

2022 ◽  
Author(s):  
Xiaohui QI ◽  
Bin CUI ◽  
Min CAO
Keyword(s):  
Genetic Variants ◽  
Plasma Cortisol ◽  
Mendelian Randomization ◽  
Class Ii ◽  
Class I ◽  
Class Iii ◽  
Reverse Causality ◽  
Obese People ◽  
Obesity Class

Abstract Context Cortisol, an important hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is associated with obesity. However, it is unclear whether the relationship between cortisol and obesity is causal or could be explained by reverse causality. Objective This work aims to assess the role of morning plasma cortisol in clinical classes of obesity. Methods In this bi-directional two-sample Mendelian Randomization (MR) study, cortisol-associated genetic variants were obtained from the CORtisol NETwork consortium (n = 12,597). The primary outcomes were obesity class I (BMI ≥ 30 kg/m 2), class II (BMI ≥ 35 kg/m 2), and class III (BMI ≥ 40kg/m 2). Inverse variance weighting (IVW) method was used as the main analysis, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, genetic variants predicting clinical classes of obesity were applied to the cortisol GWAS. Results Genetically predicted cortisol was associated with reduced risk of obesity class I (OR = 0.905; 95% CI, 0.865-0.946; p &lt; 0.001). Evidence from bi-directional MR showed that obesity class II and class III were associated with lower cortisol levels ((class II-cortisol OR = 0.953; 95% CI, 0.923-0.983; p = 0.002); (class III-cortisol OR = 0.955; 95% CI, 0.942-0.967; p &lt; 0.001)), indicating reverse causality between cortisol and obesity. Conclusions This study demonstrates that cortisol is negatively associated with obesity and vice versa. Together, these findings suggest that blunted morning plasma cortisol secretion may be responsible for severe obesity. Regulating morning plasma secretion might be a prevention measure for obese people.

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