Circulating micronutrient levels and their association with sepsis susceptibility and severity: a Mendelian randomization study
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ABSTRACT:
SUBMITTER: Wei Z
PROVIDER: S-EPMC10904592 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundLimited and inconclusive data from observational studies and randomized controlled trials exist on the levels of circulating micronutrients in the blood and their association with respiratory infections.MethodsA Mendelian randomization (MR) analysis was conducted to assess the impact of 12 micronutrients on the risk of three types of infections [upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), and pneumonia] and their 14 subtypes. This study utilized a bidirectional MR approach to evaluate causal relationships and included a range of sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. The threshold for statistical significance was set at p < 1.39 × 10-3.ResultsMeta-analysis revealed that higher levels of circulating copper were significantly associated with a reduced risk of URTI (odds ratio (OR) = 0.926, 95% CI: 0.890 to 0.964, p = 0.000195). Additionally, copper demonstrated a suggestive association with a reduced risk of LRTI (p = 0.0196), and Vitamin B6 was nominally associated with a reduced risk of pneumonia (p = 0.048). Subtype analyses further indicated several suggestive associations: copper reduces the risk of acute pharyngitis (p = 0.029), vitamin C increases the risk of critical care admissions for pneumonia (p = 0.032) and LRTI (p = 0.021), and folate reduces the risk of viral pneumonia (p = 0.042). No significant connections were observed for other micronutrients.ConclusionWe observed a genetically predicted potential protective effect of copper in susceptibility to upper respiratory infections. This provides new insights for further research into the role of micronutrients in the prevention and treatment of infection.
| S-EPMC11338864 | biostudies-literature
Project description:BackgroundObservational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR).MethodsWe performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.ResultsWe found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates.ConclusionThis MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.
| S-EPMC10616607 | biostudies-literature
Project description:BackgroundUrinary sodium was indicated to be associated with dyslipidemia, but inconsistent conclusions for this association exist across the present observational studies.ObjectivesThis study aimed to evaluate the causal association between urinary sodium and circulating lipid levels [low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol (HDL-C)] through Mendelian randomization.MethodsUnivariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) with pleiotropy-resistant methods were performed. Data for urinary sodium were obtained from the genome-wide association study (GWAS) from 446,237 European individuals. Data for lipid profiles were extracted from GWAS based on the UK Biobank (for the discovery analysis) and the Global Lipids Genetics Consortium (for the replication analysis).ResultsIn the discovery analysis, UVMR provided evidence that per 1-unit log-transformed genetically increased urinary sodium was associated with a lower level of HDL-C level (beta = -0.32; 95% CI: -0.43, -0.20; p = 7.25E-08), but not with LDL-C and triglycerides. This effect was still significant in the further MVMR when considering the effect of BMI or the other two lipid contents. In contrast, higher genetically predicted triglycerides could increase urinary sodium in both UVMR (beta = 0.030; 95% CI: 0.020, -0.039; p = 2.12E-10) and MVMR analyses (beta = 0.029; 95% CI: 0.019, 0.037; p = 8.13E-10). Similar results between triglycerides and urinary sodium were found in the replication analysis.ConclusionIncreased urinary sodium may have weak causal effects on decreased circulating HDL-C levels. Furthermore, genetically higher triglyceride levels may have independent causal effects on increased urinary sodium excretion.
| S-EPMC10716694 | biostudies-literature
Project description:BackgroundPrevious observational studies have shown conflicting results of vitamins supplementation for thyroid diseases. The causal relationships between vitamins and thyroid diseases are unclear. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to explore association of circulating vitamin levels with thyroid diseases.MethodsWe performed a bidirectional MR analysis using genome-wide association study (GWAS) data. Genetic tool variables for circulating vitamin levels include vitamins A, B9, B12, C, D, and E, Genetic tool variables of thyroid diseases include autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid nodules (TNs), and Thyroid cancer (TC). Inverse-variance weighted multiplicative random effects (IVW-RE) was mainly used for MR Analysis, weighted median (WM) and MR Egger were used as supplementary methods to evaluate the relationships between circulating vitamin levels and thyroid diseases. Sensitivity and pluripotency were evaluated by Cochran's Q test, MR-PRESSO, Radial MR, MR-Egger regression and leave-one-out analysis.ResultsPositive MR evidence suggested that circulating vitamin C level is a protective factor in autoimmune hypothyroidism (ORIVW-RE=0.69, 95%CI: 0.58-0.83, p = 1.05E-04). Reverse MR Evidence showed that genetic susceptibility to autoimmune hyperthyroidism is associated with reduced level of circulating vitamin A(ORIVW-RE = 0.97, 95% CI: 0.95-1.00, p = 4.38E-02), genetic susceptibility of TNs was associated with an increased level of circulating vitamin D (ORIVW-RE = 1.02, 95% CI: 1.00-1.03, p = 6.86E-03). No causal and reverse causal relationship was detected between other circulating vitamin levels and thyroid diseases.ConclusionOur findings provide genetic evidence supporting a bi-directional causal relationship between circulating vitamin levels and thyroid diseases. These findings provide information for the clinical application of vitamins prevention and treatment of thyroid diseases.
| S-EPMC11196410 | biostudies-literature
Project description:BackgroundCoronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which since 2019 has caused over 5 million deaths to date. The pathogenicity of the virus is highly variable ranging from asymptomatic to fatal. Evidence from experimental and observational studies suggests that circulating micronutrients may affect COVID-19 outcomes.ObjectivesTo complement and inform observational studies, we investigated the associations of genetically predicted concentrations of 12 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, vitamin D, and zinc) with SARS-CoV-2 infection risk and COVID-19 severity using Mendelian randomization (MR).MethodsTwo-sample MR was conducted using 87,870 individuals of European descent with a COVID-19 diagnosis and 2,210,804 controls from the COVID-19 host genetics initiative. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.ResultsCompared to the general population, nominally significant associations were noted for higher genetically predicted vitamin B-6 (Odds ratio per standard deviation [OR SD]: 1.06; 95% confidence interval [CI]: 1.00, 1.13; p-value = 0.036) and lower magnesium concentrations (OR SD: 0.33; 95%CI: 0.11, 0.96; P = 0.042) with COVID-19 infection risk. However, the association for magnesium was not consistent in some sensitivity analyses, and sensitivity analyses could not be performed for vitamin B-6 as only two genetic instruments were available. Genetically predicted levels of calcium, folate, β-carotene, copper, iron, vitamin B-12, vitamin D, selenium, phosphorus, or zinc were not associated with the outcomes from COVID-19 disease.ConclusionThese results, though based only on genetically predicated circulating micronutrient concentrations, provide scant evidence for possible associations of micronutrients with COVID-19 outcomes.
| S-EPMC9085481 | biostudies-literature
Project description:BackgroundThe mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development.ResultsThe causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 × 10- 6 and r2<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05-1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected.ConclusionThe MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts.
| S-EPMC9587558 | biostudies-literature
Project description:BackgroundThere 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.MethodsGenetic 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.ResultsGenetic 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.ConclusionGenetically 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.
| S-EPMC7799043 | biostudies-literature
Project description:Background: Several observational studies have demonstrated that significantly rising circulating adipokine levels are pervasive in preeclampsia or eclampsia disorder (or preeclampsia toxemia (PET)). However, it remains unclear whether this relationship is causal. In this study, we sought to elucidate the causal effects of circulating adipokine levels on PET. Methods: Summary-level data and independent genetic variants strongly associated with common adipokine molecule (adiponectin, leptin, resistin, sOB-R, and PAI-1) levels were drawn from public genome-wide association study (GWASs). Additionally, the corresponding effects between instrumental variables and PET outcomes were acquired from the FinnGen consortium, including 4,743 cases and 136,325 controls of European ancestry. Subsequently, an inverse-variance weighted (IVW) approach was applied for the principal two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Various complementary sensitivity analyses were then carried out to determine the robustness of our models. Results: The results of the IVW method did not reveal any causal relationship shared across genetically predisposed adipokine levels and PET risk (for adiponectin, OR = 0.86, 95% CI: 0.65-1.13, p = 0.274). Additionally, no significant associations were identified after taking into account five circulating adipokines in MVMR research. Complementary sensitivity analysis also supported no significant associations between them. In the reverse MR analysis, genetically predicted PET risk showed a suggestive association with elevating PAI-1 levels by the IVW method (Beta = 0.120, 95% CI: 0.014, 0.227, p = 0.026). Furthermore, there were no strong correlations between genetic liability to PET and other adipokine levels (p > 0.05). Conclusion: Our MR study did not provide robust evidence supporting the causal role of common circulating adipokine levels in PET, whereas genetically predicted PET may instrumentally affect PAI-1 levels. These findings suggest that PAI-1 may be a useful biomarker for monitoring the diagnosis or therapy of PET rather than a therapeutic target for PET.
| S-EPMC9444139 | biostudies-literature
Project description:Observational data from China, the United States, France, and Italy suggest that chronological age is an adverse COVID-19 outcome risk factor, with older patients having a higher severity and mortality rate than younger patients. Most studies have gotten the same view. However, the role of aging in COVID-19 adverse effects is unclear. To more accurately assess the effect of aging on adverse COVID-19, we conducted this bidirectional Mendelian randomization (MR) study. Epigenetic clocks and telomere length were used as biological indicators of aging. Data on epigenetic age (PhenoAge, GrimAge, Intrinsic HorvathAge, and HannumAge) were derived from an analysis of biological aging based on genome-wide association studies (GWAS) data. The telomere length data are derived from GWAS and the susceptibility and severity data are derived from the COVID-19 Host Genetics Initiative (HGI). Firstly, epigenetic age and telomere length were used as exposures, and following a screen for appropriate instrumental variables, we used random-effects inverse variance weighting (IVW) for the main analysis, and combined it with other analysis methods (e.g., MR Egger, Weighted median, simple mode, Weighted mode) and multiple sensitivity analysis (heterogeneity analysis, horizontal multiplicity analysis, "leave-one-out" analysis). For reducing false-positive rates, Bonferroni corrected significance thresholds were used. A reverse Mendelian randomization analysis was subsequently performed with COVID-19 susceptibility and severity as the exposure. The results of the MR analysis showed no significant differences in susceptibility to aging and COVID-19. It might suggest that aging is not a risk factor for COVID-19 infection (P-values are in the range of 0.05-0.94). According to the results of our analysis, we found that aging was not a risk factor for the increased severity of COVID-19 (P > 0.05). However, severe COVID-19 can cause telomere lengths to become shorter (beta = -0.01; se = 0.01; P = 0.02779). In addition to this, severe COVID-19 infection can slow the acceleration of the epigenetic clock "GrimAge" (beta = -0.24, se = 0.07, P = 0.00122), which may be related to the closely correlation of rs35081325 and COVID-19 severity. Our study provides partial evidence for the causal effects of aging on the susceptibility and severity of COVID-19.
| S-EPMC9538153 | biostudies-literature
Project description: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.
| S-EPMC8656944 | biostudies-literature