scholarly journals Relationship of Soluble Interleukin-6 Receptors With Asthma: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Yoshihiko Raita ◽  
Zhaozhong Zhu ◽  
Carlos A. Camargo ◽  
Robert J. Freishtat ◽  
Debby Ngo ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Study Data ◽  
Sensitivity Analyses ◽  
Receptor Level ◽  
Inverse Variance ◽  
Interleukin 6 Receptor ◽  
The Uk

Purpose: Emerging evidence suggests a potential role of interleukin-6 pathways—trans-signaling with soluble interleukin-6 receptors—in the asthma pathobiology. Despite the evidence for their associations with asthma, the causal role of soluble interleukin-6 receptors remains uncertain. We investigated the relations of soluble interleukin-6 receptors with asthma and its major phenotypes.Methods: We conducted a two-sample Mendelian randomization study. As genetic instruments, we selected 33 independent cis-acting variants strongly associated with the level of plasma soluble interleukin-6 receptor in the INTERVAL study. To investigate the association of variants with asthma and its phenotypes, we used genome-wide association study data from the UK Biobank. We combined variant-specific causal estimates by the inverse-variance weighted method for each outcome.Results: Genetically-instrumented soluble interleukin-6 receptor level was associated with a significantly higher risk of overall asthma (OR per one standard deviation increment in inverse-rank normalized soluble interleukin-6 receptor level, 1.02; 95%CI, 1.01–1.03; P = 0.004). Sensitivity analyses demonstrated consistent results and indicated no directional pleiotropy—e.g., MR-Egger (OR, 1.03; 95%CI, 1.01–1.05; P = 0.002; Pintercept =0.37). In the stratified analysis, the significant association persisted across asthma phenotypes—e.g., childhood asthma (OR, 1.05; 95%CI, 1.02–1.08; P < 0.001) and obese asthma (OR, 1.02; 95%CI 1.01–1.03; P = 0.007). Sensitivity analysis using 16 variants selected with different thresholds also demonstrated significant associations with overall asthma and its phenotypes.Conclusion: Genetically-instrumented soluble interleukin-6 receptor level was causally associated with modestly but significantly higher risks of asthma and its phenotypes. Our observations support further investigations into identifying specific endotypes in which interleukin-6 pathways may play major roles.

scholarly journals Mendelian randomization analysis of the association between human blood cell traits and uterine polyps

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shuliu Sun ◽  
Yan Liu ◽  
Lanlan Li ◽  
Minjie Jiao ◽  
Yufen Jiang ◽  
...  
Keyword(s):  
Human Blood ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Random Effect ◽  
Sensitivity Analyses ◽  
Endometrial Polyps ◽  
Inverse Variance ◽  
Weighted Median ◽  
The Uk ◽  
Uterine Polyps

AbstractHuman blood cells (HBCs) play essential roles in multiple biological processes but their roles in development of uterine polyps are unknown. Here we implemented a Mendelian randomization (MR) analysis to investigate the effects of 36 HBC traits on endometrial polyps (EPs) and cervical polyps (CPs). The random-effect inverse-variance weighted method was adopted as standard MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Genetic instruments of HBC traits was extracted from a large genome-wide association study of 173,480 individuals, while data for EPs and CPs were obtained from the UK Biobank. All samples were Europeans. Using genetic variants as instrumental variables, our study found that both eosinophil count (OR 0.85, 95% CI 0.79–0.93, P = 1.06 × 10−4) and eosinophil percentage of white cells (OR 0.84, 95% CI 0.77–0.91, P = 2.43 × 10−5) were associated with decreased risk of EPs. The results were robust in sensitivity analyses and no evidences of horizontal pleiotropy were observed. While we found no significant associations between HBC traits and CPs. Our findings suggested eosinophils might play important roles in the pathogenesis of EPs. Besides, out study provided novel insight into detecting uterine polyps biomarkers using genetic epidemiology approaches.

scholarly journals Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Li Qian ◽  
Yajuan Fan ◽  
Fengjie Gao ◽  
Binbin Zhao ◽  
Bin Yan ◽  
...  
Keyword(s):  
Uric Acid ◽  
Lower Risk ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Strong Predictor ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Inverse Variance

Abstract Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

scholarly journals Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Chunyu Li ◽  
Ruwei Ou ◽  
Qianqian Wei ◽  
Huifang Shang
Keyword(s):  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Carnitine Level ◽  
Standard Deviation Increase ◽  
Inverse Variance ◽  
Weighted Median ◽  
Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

scholarly journals Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Wang ◽  
Hui Deng ◽  
Yihuai Pan ◽  
Lijian Jin ◽  
Rongdang Hu ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Host Susceptibility ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

scholarly journals Blood Pressure and Risk of Cardiovascular Disease in UK Biobank

Hypertension ◽  
2021 ◽  
Author(s):  
Eric Yuk Fai Wan ◽  
Wing Tung Fung ◽  
C. Mary Schooling ◽  
Shiu Lun Au Yeung ◽  
Man Ki Kwok ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Randomization Test ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
Uk Biobank ◽  
Cvd Risk ◽  
The Uk

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

scholarly journals Periodontitis and pulmonary function: a Mendelian randomization study

2021 ◽  
Author(s):  
Sebastian-Edgar Baumeister ◽  
Michael Nolde ◽  
Birte Holtfreter ◽  
Hansjörg Baurecht ◽  
Sven Gläser ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Forced Expiratory Volume ◽  
Sensitivity Analyses ◽  
Observational Research ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
The Uk

Abstract Objectives Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function. Materials and methods We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10−6) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium. Results MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) =  − 0.004 (− 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates. Conclusions Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function. Clinical relevance Periodontitis does not seem to be a risk factor for worsening of pulmonary function.

Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization

Rheumatology ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 940-947 ◽  
Author(s):  
Zhen Zeng ◽  
Wanting Zhang ◽  
Yu Qian ◽  
Huijun Huang ◽  
David J H Wu ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome ◽  
Mean Differences

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.

scholarly journals Causal Associations between Serum Urea and Cancer: A Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 498
Author(s):  
Yandi Sun ◽  
Jingjia Li ◽  
Zihao Qu ◽  
Ze Yang ◽  
Xueyao Jia ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Serum Urea ◽  
Urea Level ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
First Time

Urea is largely derived from the urea cycle reactions through hepatic detoxification of free ammonia and cleared by urination, and the serum urea level is a crucial medical indicator for measuring the kidney function in patients with nephropathy; however, investigative revelations pointing to the serum urea level as a risk factor for cancer are very scarce, and relevant studies are restricted by potential biases. We aimed to explore the causal relationships of the serum urea level with cancer development by focusing on renal cell carcinoma (RCC) using the Mendelian randomization (MR) analyses. Summary estimates were collected from the inverse-variance weighted (IVW) method based on six single nucleotide polymorphisms (SNPs). The selected SNPs related to the serum urea were obtained from a large genome-wide association study (GWAS) of 13,312 European participants. The summary statistics of RCC were also available from public databases (IARC, n = 5219 cases, n = 8011 controls). Sensitivity analyses included the weighted median and MR-Egger methods. Serum urea was inversely associated with RCC in females (effect = 1.93; 95% CI: 1.24 to 3.01; p = 0.004) but exhibited null association with RCC in males, breast cancer (BRCA) in both genders and prostate cancer (PCa) in males. Similar conclusions were also drawn from the weighted median and MR-Egger. These findings reveal an intriguing link between serum urea and cancer risks for the very first time. Without ambiguity, the serum urea is causatively related to RCC specifically in females, although the mechanism(s) by which urea is involved in RCC development remains to be experimentally/clinically investigated. Our studies may well provide novel insights for RCC diagnosis, intervention and/or therapy.

scholarly journals Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Di He ◽  
Liying Cui
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mendelian Randomization ◽  
Epidemiologic Studies ◽  
European Population ◽  
Causal Role ◽  
Sensitivity Analyses ◽  
Current Evidence ◽  
Inverse Variance ◽  
Lateral Sclerosis

Objectives: The relation between selenium overexposure and increased risk of amyotrophic lateral sclerosis (ALS) has been subject to considerable interest. Epidemiologic studies have reported suggestive associations between selenium and ALS, although the causal inference between selenium and ALS remains to be established.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to analyze the causal role of selenium on ALS risk. Variants associated with selenium levels were obtained from the GWAS meta-analysis of circulating selenium levels (n = 5,477) and toenail selenium levels (n = 4,162) in the European population. Outcome data were from the largest ALS GWAS dataset with 20,806 ALS cases and 59,804 controls in the European population. Inverse variance weighted (IVW) method was used as the main analysis, with an array of sensitivity analyses performed to detect potential violations of MR assumptions.Results: Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in ALS development (odds ratio (OR) = 1.02, 95% confidence interval (CI) = 0.96–1.08). Similar results were observed for the sensitivity analyses (OR = 1.00, 95% CI = 0.95–1.07 for weighted median; OR = 1.07, 95% CI = 0.87–1.32 for MR-Egger), with no pleiotropy detected.Conclusions: Although selenium was found associated with ALS according to earlier epidemiologic studies, current evidence based on the population of European ancestry does not support the causal effect of selenium on ALS risk.

scholarly journals Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengyu Li ◽  
Chris Ho Ching Yeung ◽  
C. Mary Schooling
Keyword(s):  
Immune System ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Multiple Comparisons ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inflammatory Protein ◽  
Inverse Variance ◽  
System Functioning

BackgroundImmune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.MethodsWe assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).ResultsMacrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96–0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89–0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.ConclusionA crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.

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