scholarly journals The effect of angiotensin-converting enzyme levels on Covid-19 susceptibility and severity: a Mendelian randomization study

2020 ◽  
Author(s):  
Guillaume Butler-Laporte ◽  
Tomoko Nakanishi ◽  
Vincent Mooser ◽  
Alessandra Renieri ◽  
Sara Amitrano ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ace Inhibitors ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Severe Disease ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Converting Enzyme ◽  
Discontinue Therapy

Abstract Background There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the Covid-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or Covid-19 severity, while reducing potential bias from confounding and reverse causation in observational studies. Methods Genetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for Covid-19 susceptibility, hospitalization and severe-disease outcome. Results Genetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in Covid-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results. Conclusion Genetically decreased serum ACE levels were not associated with susceptibility to, or severity of, Covid-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the Covid-19 pandemic.

scholarly journals Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity

2022 ◽  
Vol 12 ◽  
Author(s):  
Li-Juan Qiu ◽  
Kang-Jia Yin ◽  
Gui-Xia Pan ◽  
Jing Ni ◽  
Bin Wang
Keyword(s):  
Severe Asthma ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Severe Disease ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide ◽  
Inverse Variance ◽  
Increased Risk

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity.Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted.Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses.Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

scholarly journals Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

PLoS Medicine ◽  
2021 ◽  
Vol 18 (6) ◽  
pp. e1003605
Author(s):  
Guillaume Butler-Laporte ◽  
Tomoko Nakanishi ◽  
Vincent Mooser ◽  
David R. Morrison ◽  
Tala Abdullah ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Severe Disease ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Logarithmic Scale ◽  
Host Genetics ◽  
A Genome ◽  
Vitamin D Levels

Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. Conclusions In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

scholarly journals Atrial fibrillation and kidney function: A bidirectional Mendelian randomization study

2020 ◽  
Author(s):  
Sehoon Park ◽  
Soojin Lee ◽  
Yaerim Kim ◽  
Yeonhee Lee ◽  
Min Woo Kang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Kidney Function ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Individual Level ◽  
Level Data ◽  
Lower Egfr

Aims: To investigate the causal effects between atrial fibrillation (AF) and kidney function. Methods and Results: We performed a bidirectional Mendelian randomization (MR) analysis implementing the results from large-scale genome-wide association study (GWAS) for estimated glomerular filtration rate (eGFR) by the CKDGen (N = 1,046,070) and for AF (N = 588,190) to determine genetic instruments. A bidirectional two-sample MR based on summary-level data was performed. Inverse variance weighted method was the main MR method. For replication, an allele-score based MR was performed by individual-level data within the UK Biobank cohort of white British ancestry with eGFR values (N= 321,260). The genetical predisposition to AF was significantly associated with lower eGFR [beta -0.002 (standard error 0.0005), P < 0.001] and higher risk of chronic kidney disease [beta 0.051 (0.012), P < 0.001], and the significance remained in various MR sensitivity analyses. The causal estimates were consistent when we limited the analysis to individuals of European ancestry. The genetically predicted eGFR did not show significant association with risk of AF [beta -0.189 (0.184), P = 0.305]. The results were similar in allele-score based MR, as allele-score for AF was significantly associated with lower eGFR [beta -0.069 (0.021), P < 0.001] but allele-score for eGFR did not show significant association with risk of AF [beta -0.001 (0.009), P = 0.907]. Conclusions: Our study supports that genetical predisposition to AF is a causal risk factor for kidney function impairment. However, effect from kidney function on AF was not identified in this study.

scholarly journals A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

2019 ◽  
Vol 294 (25) ◽  
pp. 9760-9770 ◽  
Author(s):  
Shuyu Liu ◽  
Fujiko Ando ◽  
Yu Fujita ◽  
Junjun Liu ◽  
Tomoji Maeda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Precursor Protein ◽  
Causative Role ◽  
Converting Enzyme ◽  
Clinical Dose

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

scholarly journals Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1940
Author(s):  
Karl Michaëlsson ◽  
Susanna C. Larsson
Keyword(s):  
Bone Mineral Density ◽  
Confidence Interval ◽  
Bone Mineral ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Alpha Tocopherol ◽  
European Ancestry ◽  
Mineral Density ◽  
Standard Deviation Increase ◽  
A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

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