High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

Download Full-text

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

10.21203/rs.3.rs-885601/v1 ◽

2021 ◽

Author(s):

Kailin Xia ◽

Linjing Zhang ◽

Lu Tang ◽

Tao Huang ◽

Dongsheng Fan

Keyword(s):

Blood Pressure ◽

Amyotrophic Lateral Sclerosis ◽

Protective Factor ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Inverse Variance ◽

High Level ◽

Lateral Sclerosis

Abstract Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

Download Full-text

Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.811699 ◽

2022 ◽

Vol 12 ◽

Author(s):

Changqing Mu ◽

Yating Zhao ◽

Chen Han ◽

Dandan Tian ◽

Na Guo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Large Scale ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance ◽

Effective Role ◽

Copper Zinc ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.

Download Full-text

Physical activity and risk of Alzheimer’s disease: a two-sample Mendelian randomization study

10.1101/819821 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sebastian E Baumeister ◽

André Karch ◽

Martin Bahls ◽

Alexander Teumer ◽

Michael F Leitzmann ◽

...

Keyword(s):

Physical Activity ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Observational Studies ◽

Protective Factor ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Inverse Variance

ABSTRACTIntroductionEvidence from observational studies for the effect of physical activity on the risk of Alzheimer’s disease (AD) is inconclusive. We performed Mendelian randomization analysis to examine whether physical activity is a protective factor for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were identified using PubMed and the GWAS catalog. The study population included 21,982 AD cases and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNP) known at P < 5×10−8 to be associated with accelerometer-assessed physical activity served as instrumental variables.ResultsGenetically predicted accelerometer-assessed physical activity had no effect on the risk of AD (inverse variance weighted odds ratio [OR] per standard deviation (SD) increment: 1.03, 95% confidence interval: 0.97-1.10, P=0.332).DiscussionThe present study does not support a relationship between physical activity and risk of AD, and suggests that previous observational studies might have been biased.

Download Full-text

Causal relationship between years of education and the occurrence of rheumatoid arthritis

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2018-136374 ◽

2019 ◽

Vol 95 (1125) ◽

pp. 378-381 ◽

Cited By ~ 3

Author(s):

Sang-Cheol Bae ◽

Young Ho Lee

Keyword(s):

Rheumatoid Arthritis ◽

Association Studies ◽

Meta Analysis ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Causative Relationship ◽

Weighted Median ◽

The Uk ◽

Education And Development

ObjectiveTo search out whether or not years of education is causally related to rheumatoid arthritis (RA).MethodWe conducted a two-sample Mendelian randomisation (MR) analysis employing inverse-variance weighted (IVW), weighted median and MR-Egger regression analysis. We chose statistic data of years of education from the UK Biobank genome-wide association studies (GWASs) (n=293 723) as the exposure and a meta-analysis of GWASs of RA with autoantibody (n=5539) and European controls (n=20 169) as the outcome.ResultsWe selected a total of 49 single nucleotide polymorphisms as instrumental variables (IVs). The IVW method instructed an inverse causative relationship between years of education and RA (β=− 0.039, SE=0.283, p=0.008). MR-Egger regression test showed that directional pleiotropy seems not to bias the MR results (intercept=0.028; p=0.358). MR-Egger analysis demonstrated no causative relationship between RA and years of education (β=− 2.320, SE=1.709, p=0.181). However, the weighted median approach indicated a causative association between RA and years of education (β=−0.950, SE=0.355, p=0.008).ConclusionsThe MR analysis supported a potential inverse causative relationship between years of education and development of RA.

Download Full-text

Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy

European Heart Journal ◽

10.1093/eurheartj/ehz646 ◽

2019 ◽

Vol 40 (42) ◽

pp. 3459-3470 ◽

Cited By ~ 31

Author(s):

Marta Czesnikiewicz-Guzik ◽

Grzegorz Osmenda ◽

Mateusz Siedlinski ◽

Richard Nosalski ◽

Piotr Pelka ◽

...

Keyword(s):

Blood Pressure ◽

Causal Relationship ◽

Mendelian Randomization ◽

Association Studies ◽

Controlled Trial ◽

Substantial Reduction ◽

Periodontal Treatment ◽

Genome Wide Association Studies ◽

Hypertensive Patients ◽

Periodontal Status

Abstract Aims Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. Methods and results We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of −11.1 mmHg; 95% CI 6.5–15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. Conclusion A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.

Download Full-text

Life Course Adiposity and Alzheimer’s Disease: A Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210345 ◽

2021 ◽

pp. 1-10

Author(s):

Xian Li ◽

Yan Tian ◽

Yu-Xiang Yang ◽

Ya-Hui Ma ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Life Course ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Fat Percentage ◽

Regression Methods ◽

Weighted Median

Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01–1.05, p = 2.7×10–3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90–0.98, p = 1.8×10–3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00–1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00–1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.

Download Full-text

Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

Download Full-text

Comorbidities and Susceptibility to COVID-19: A Generalized Gene Set Data Mining Approach

Journal of Clinical Medicine ◽

10.3390/jcm10081666 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1666

Author(s):

Micaela F. Beckman ◽

Farah Bahrani Mougeot ◽

Jean-Luc C. Mougeot

Keyword(s):

Protein Interactions ◽

Association Studies ◽

Meta Analysis ◽

Holistic Approach ◽

Gene Interaction ◽

Snp Analysis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Protein Protein Interactions ◽

Data Mining Approach

The COVID-19 pandemic has led to over 2.26 million deaths for almost 104 million confirmed cases worldwide, as of 4 February 2021 (WHO). Risk factors include pre-existing conditions such as cancer, cardiovascular disease, diabetes, and obesity. Although several vaccines have been deployed, there are few alternative anti-viral treatments available in the case of reduced or non-existent vaccine protection. Adopting a long-term holistic approach to cope with the COVID-19 pandemic appears critical with the emergence of novel and more infectious SARS-CoV-2 variants. Our objective was to identify comorbidity-associated single nucleotide polymorphisms (SNPs), potentially conferring increased susceptibility to SARS-CoV-2 infection using a computational meta-analysis approach. SNP datasets were downloaded from a publicly available genome-wide association studies (GWAS) catalog for 141 of 258 candidate COVID-19 comorbidities. Gene-level SNP analysis was performed to identify significant pathways by using the program MAGMA. An SNP annotation program was used to analyze MAGMA-identified genes. Differential gene expression was determined for significant genes across 30 general tissue types using the Functional and Annotation Mapping of GWAS online tool GENE2FUNC. COVID-19 comorbidities (n = 22) from six disease categories were found to have significant associated pathways, validated by Q–Q plots (p < 0.05). Protein–protein interactions of significant (p < 0.05) differentially expressed genes were visualized with the STRING program. Gene interaction networks were found to be relevant to SARS and influenza pathogenesis. In conclusion, we were able to identify the pathways potentially affected by or affecting SARS-CoV-2 infection in underlying medical conditions likely to confer susceptibility and/or the severity of COVID-19. Our findings have implications in future COVID-19 experimental research and treatment development.

Download Full-text

Causal Inference Between Chronic Periodontitis and Chronic Kidney Disease: A Bidirectional Mendelian Randomization Analysis in a European Population

Frontiers in Genetics ◽

10.3389/fgene.2021.676136 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jie Yang ◽

Tianyi Chen ◽

Yahong Zhu ◽

Mingxia Bai ◽

Xingang Li

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Causal Inference ◽

Causal Relationship ◽

Instrumental Variables ◽

Chronic Periodontitis ◽

Mendelian Randomization ◽

Association Studies ◽

Genome Wide Association Studies ◽

Summary Statistics

BackgroundPrevious epidemiological studies have shown significant associations between chronic periodontitis (CP) and chronic kidney disease (CKD), but the causal relationship remains uncertain. Aiming to examine the causal relationship between these two diseases, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis with multiple MR methods.MethodsFor the casual effect of CP on CKD, we selected seven single-nucleotide polymorphisms (SNPs) specific to CP as genetic instrumental variables from the genome-wide association studies (GWAS) in the GLIDE Consortium. The summary statistics of complementary kidney function measures, i.e., estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN), were derived from the GWAS in the CKDGen Consortium. For the reversed causal inference, six SNPs associated with eGFR and nine with BUN from the CKDGen Consortium were included and the summary statistics were extracted from the CLIDE Consortium.ResultsNo significant causal association between genetically determined CP and eGFR or BUN was found (all p > 0.05). Based on the conventional inverse variance-weighted method, one of seven instrumental variables supported genetically predicted CP being associated with a higher risk of eGFR (estimate = 0.019, 95% CI: 0.012–0.026, p < 0.001).ConclusionEvidence from our bidirectional causal inference does not support a causal relation between CP and CKD risk and therefore suggests that associations reported by previous observational studies may represent confounding.

Download Full-text

Association of Physical Activity with Body Composition: A Mendelian Randomization Study

10.31219/osf.io/e3mrx ◽

2021 ◽

Author(s):

Ferris Alaa Ramadan ◽

Katherine Ellingson ◽

Yann Klimentidis

Keyword(s):

Physical Activity ◽

Body Composition ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Dietary Interventions ◽

The Uk

Background. Studies suggest that body composition can be improved through physical activity (PA) independently of dietary interventions. A separate line of evidence suggests that PA may reduce high-risk visceral adipose tissue (VAT), without clinically meaningful weight change. Genome-wide association studies have previously identified genetic markers associated with PA behaviors and may provide an opportunity to evaluate hypothesized causal relationships with body composition. Methods. We performed a Mendelian randomization (MR) study to test the incremental benefits of various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (LBM) (kg), body fat (%), and VAT (kg). Genetic instruments were identified for both self-reported and accelerometer-measured PA, including sedentary behavior. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest publicly available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects.Results. We did not identify associations between genetically-predicted sedentary behavior (self-reported or accelerometer) and body composition outcomes in MVMR analyses. All analyses for self-reported moderate PA were null for body composition outcomes, including BMI, LBM and VAT. Genetically-predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR β = -0.15, 95% Confidence Interval (CI): -0.24, -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR β = -0.27, 95%CI: -0.52, -0.01, p=0.034), and was robust across several sensitivity analyses. Conclusions. We did not identify evidence of a causal relationship between genetically-predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

Download Full-text