Role of inflammatory biomarkers in mediating the effect of lipids on spontaneous intracerebral hemorrhage: a two-step, two-sample Mendelian randomization study
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SUBMITTER: Huang M
PROVIDER: S-EPMC11337198 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundObservational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway.MethodsWe utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings.ResultsThe Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929-0.972, p = 6.65 × 10- 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906-0.971, p = 2.79 × 10- 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906-0.969, p = 1.48 × 10- 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876-0.961, p = 2.72 × 10- 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028-1.079, p = 2.11 × 10- 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039-1.135, p = 2.47 × 10- 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%.ConclusionOur research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.
| S-EPMC11193249 | biostudies-literature
Project description:BackgroundPsychiatric traits have been associated with intracerebral hemorrhage (ICH) in observational studies, although their causal relationships remain uncertain. We used Mendelian randomization analyses to infer causality between psychiatric traits and ICH.MethodsWe collected data from genome-wide association studies of ICH (n = 361,194) and eight psychiatric traits among Europeans, including mood swings (n = 451,619), major depressive disorder (n = 480,359), attention-deficit/hyperactivity disorder (n = 53,293), anxiety (n = 459,560), insomnia (n = 462,341), schizophrenia (n = 77,096), neuroticism (n = 374,323), and bipolar disorder (n = 51,710). We performed a series of bidirectional two-sample Mendelian randomization and related sensitivity analyses. A Bonferroni corrected threshold of p < 0.00625 (0.05/8) was considered to be significant, and p < 0.05 was considered suggestive of evidence for a potential association.ResultsMendelian randomization analyses revealed suggestive positive causality of mood swings on ICH (odds ratio = 1.006, 95% confidence interval = 1.001-1.012, p = 0.046), and the result was consistent after sensitivity analysis. However, major depressive disorder (p = 0.415), attention-deficit/hyperactivity disorder (p = 0.456), anxiety (p = 0.664), insomnia (p = 0.699), schizophrenia (p = 0.799), neuroticism (p = 0.140), and bipolar disorder (p = 0.443) are not significantly associated with the incidence of ICH. In the reverse Mendelian randomization analyses, no causal effects of ICH on mood swings (p = 0.565), major depressive disorder (p = 0.630), attention-deficit/hyperactivity disorder (p = 0.346), anxiety (p = 0.266), insomnia (p = 0.102), schizophrenia (p = 0.463), neuroticism (p = 0.261), or bipolar disorder (p = 0.985) were found.ConclusionOur study revealed that mood swings are suggestively causal of ICH and increase the risk of ICH. These results suggest the clinical significance of controlling mood swings for ICH prevention.
| S-EPMC9850495 | biostudies-literature
Project description:BackgroundIntracerebral hemorrhage (ICH) is a severe form of stroke with high mortality and limited treatment options. While traditional risk factors like hypertension have been well-studied, the role of emotional states as acute triggers for ICH remains unclear. This study employs Mendelian Randomization (MR) to investigate the causal relationship between emotional traits of worry and anxiety and the incidence of ICH.MethodsWe used a two-sample MR approach, leveraging summary-level data from genome-wide association studies (GWAS) for emotional traits and ICH. The primary analysis was conducted using the Inverse-Variance Weighted (IVW) method, supplemented by multiple sensitivity analyses including Maximum Likelihood and MR PRESSO methods.ResultsOur MR analysis revealed a robust and significant causal relationship between the emotional trait "Worrier/anxious feelings" and ICH, supported by 195 instrumental variables (SNPs). The odds ratio (OR) was 2.98 (95% CI: 1.16, 7.61) with a p-value of 0.0229. Sensitivity analyses corroborated these findings, enhancing the reliability of our results. In contrast, other emotional traits such as "Nervous feelings" and "Sensitivity/hurt feelings" did not show significant associations, reinforcing the specificity of our primary finding.ConclusionOur study provides compelling evidence for a causal relationship between the emotional traits of worry and anxiety and the incidence of ICH, offering a new dimension in our understanding of this devastating condition and paving the way for more nuanced risk stratification and preventive strategies.
| S-EPMC11222637 | biostudies-literature
Project description:In view of the current debate about the relationship between lipids and deep venous thrombosis (DVT) in clinical studies, a two-sample Mendelian randomization (MR) study was conducted to clarify the effects of five circulating lipids (apolipoprotein A1, apolipoprotein B, low-density lipoprotein, high-density lipoprotein and triglycerides) on DVT from the perspective of genetic inheritance. Five lipids (exposure) were analysed by MR with DVT (outcome) from two different data sources. For the analysis, we used inverse variance weighting and a weighted mode, weighted median, simple mode and MR-Egger regression to analyse the effect of circulating lipids on DVT. In addition, we used the MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis to evaluate horizontal multiplicity, heterogeneity and stability, respectively, in the analysis. In the analysis, the two-sample Mendelian randomization analysis of five common circulating lipids and DVT showed that common circulating lipids had no causal effect on DVT, which is somewhat inconsistent with the findings of many published observational studies. Based on our results, our two-sample MR analysis failed to detect a statistically significant causal relationship between five common circulating lipids and DVT.
| S-EPMC10167313 | biostudies-literature
Project description:Aims/hypothesis20-80% of Nonalcoholic Fatty Liver Disease (NAFLD) have been observed to have dyslipidemia. Nevertheless, the probable mechanism of dyslipidemia's effect on NAFLD remains unclear. Mendelian randomization (MR) was utilized to investigate the relationship between lipids, inflammatory factors, and NAFLD; and also, to determine the proportion mediated by interleukin-17(IL-17) and interleukin-1β(IL-1β) for the effect between lipids and NAFLD.MethodsSummary statistics of traits were obtained from the latest and largest genome-wide association study (GWAS). The UK Biobank provided a summary of lipid statistics, which comprised up to 500,000 participants of European descent. And NAFLD GWAS summary statistics were obtained from the FinnGen Biobank which included a total sample size of 218,792 participants of European ancestry. In order to gain an overall picture of how lipids affect NAFLD, MR with two samples was carried out. Multivariable MR determined lipids direct effects on NAFLD after adjusting for inflammatory factors, namely IL-1β, interleukin-6(IL-6), interleukin-16(IL-16), IL-17, and interleukin-18(IL-18); those lipids comprise HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). For the purpose of determining the MR impact, an inverse variance weighted (IVW) meta-analysis of each Wald Ratio was carried out, while other methods were also performed for sensitivity analysis.ResultsWe discovered a positive association between genetically predicted TGs levels and a 45.5% elevated risk of NAFLD, while genetically predicted IL-1β [(IVW: OR 1.315 (1.060-1.630), p = 0.012) and IL-17 [(IVW: OR 1.468 (1.035-2.082), p = 0.032] were positively associated with 31.5% and 46.8% increased risk of NAFLD, respectively. Moreover, TG was positively associated with 10.5% increased risk of IL-1β and 17.3% increased risk of IL-17. The proportion mediated by IL-17 and IL-1β respectively and both was 2.6%, 3.1%, 14.1%.ConclusionGenetically predicted TGs, IL-1β, and IL-17 were positively associated with increased risk of NAFLD, with evidence that IL-1β and IL-17 mediated TGs effect upon NAFLD risk. It indicated that early diet management, weight management, lipid-lowering and anti-inflammatory treatment should be carried out for patients with hyperlipidemia to prevent the NAFLD.
| S-EPMC9609493 | biostudies-literature
Project description:ObjectiveInvestigating the causal connection that exists between inflammatory bowel disease (IBD) and hypertension (HT). To gain a deeper insight into the correlation among IBD, gut microbiota, and HT, we conducted a two-step, two-sample Mendelian randomization study.MethodsAn investigation of genome-wide association study (GWAS) summary-level data was utilized to conduct a two-sample Mendelian randomization (MR) analysis of genetically predicted inflammatory bowel disease: (12,882cases, 21,770controls) on Systolic/Diastolic blood pressure (N = 2,564). Subsequently, two-step MR analyses revealed that the relationship between IBD and SBP was partly mediated by Faecalicatena glycyrrhizinilyticum. The robustness of the findings was confirmed through several sensitivity assessments.ResultsThis MR study showed that increase in genetically predicted IBD was associated with higher risk of genetically predicted SBP (OR: 1.08, 95% CI: 1.01-1.16, P < 0.05) and DBP (OR: 1.09, 95% CI: 1.02-1.17, P < 0.05), respectively. Inverse variance weighted (IVW) MR analysis also showed that increase in genetically predicted IBD was associated with higher abundance Faecalicatena glycyrrhizinilyticum (OR: 1.03, 95% CI: 1.01-1.04, P < 0.05), which subsequently associated with increased SBP risk (OR: 1.42, 95% CI: 1.06-1.9, P < 0.05). Faecalicatena glycyrrhizinilyticum abundance in stool was responsible for mediating 11% of the genetically predicted IBD on SBP.ConclusionThe research proposed a causal link between Inflammatory Bowel Disease (IBD) and Hypertension (HT), with a little percentage of the impact being influenced by Faecalicatena glycyrrhizinilyticum in stool. Mitigating gut microbiome may decrease the heightened risk of hypertension in people with inflammatory bowel disease.
| S-EPMC11521848 | biostudies-literature
Project description:Purpose: To investigate the potential causal relationship between coffee consumption and osteoarthritis (OA), and to disentangle whether body mass index (BMI) and Bone mineral density (BMD) mediate this relationship. Methods: We performed two-sample and two-step Mendelian randomization (MR) analyses utilizing publicly available genome-wide association studies (GWAS) summary statistics to estimate the association between coffee intake and OA risk (including knee OA, hip OA, knee or hip OA, and total OA), as well as the possible mediating effects of BMI and BMD. In addition, data of different coffee types (decaffeinated coffee, instant coffee, ground coffee-including espresso, filter, etc., and other coffee types) were used to explore the effect of coffee type on the risk of OA. Results: In two-sample MR, coffee intake increased the risk of OA in various sites, with the most significant impact observed in knee osteoarthritis (KOA) (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.57-2.61, p < 0.001). The effect on self-reported OA was minimal (OR 1.03, 95% CI 1.01-1.05, p = 0.006). Further analysis of different types of coffee revealed that only decaffeinated coffee was causally associated with both KOA (OR 4.40, 95% CI 1.71-11.33, p = 0.002) and self-reported OA (OR 1.13, 95% CI 1.02-1.26, p = 0.022). In two-step MR, BMI explained over half of the coffee intake-all OA risk association, while BMD accounted for less than 5% of the mediation effect. Conclusion: Our study suggests that coffee intake increase the risk of OA, with BMI playing a significant mediating role. Decaffeinated coffee appears to have the greatest impact on OA risk compared to other types of coffee. Therefore, managing BMI and selecting appropriate types of coffee should be included in the health management of individuals who frequently consume coffee.
| S-EPMC10867243 | biostudies-literature
Project description:BackgroundAlthough research has indicated correlations between lipids, cerebrospinal fluid (CSF) metabolites, and Late-Onset Alzheimer's Disease (LOAD), the specific causal relationships among these elements, as well as the roles and mechanisms of the cerebrospinal fluid metabolites, remain unclear.MethodsStatistical datasets derived from Genome-Wide Association Studies (GWAS) were utilized to assess the bidirectional causal relationships between lipids and LOAD. Subsequently, genetic variants associated with CSF metabolites and established lipids underwent a two-step Mendelian randomization (MR) analysis to explore potential mediators and analyze mediation effects. Sensitivity analyses were employed to assess the robustness of the detection systems.ResultsGenetically predicted cholesterol (IVW OR = 0.989; 95% CI 0.982-0.996) was found to reduce the risk of LOAD, whereas Phosphatidylcholine (PC) (18:1_0:0) (IVW OR = 1.015; 95% CI 1.005-1.025) posed a risk factor. The potential mediator, CSF metabolite N-acetylneuraminate (NeuAC), was identified with a mediation proportion of 21.02% (3.25%, 45.50%). No pleiotropy or heterogeneity was detected across MR analyses.ConclusionsThe findings underscore the pivotal role of CSF metabolomics in elucidating the lipid-mediated pathogenesis of LOAD, highlighting potential diagnostic and preventative biomarkers.
| S-EPMC11603644 | biostudies-literature
Project description:ObjectiveThe objective of this study is to investigate the roles of cardiometabolic factors (including blood pressure, blood lipids, thyroid function, body mass, and insulin sensitivity) in mediating the causal effect of type 2 diabetes (T2DM) on cardiovascular disease (CVD) outcomes.DesignTwo-step, two-sample multivariable Mendelian randomization (MVMR) study.SettingInternational genome-wide association study (GWAS) consortia data.ExposureType 2 diabetes, blood pressure: systolic blood pressure (SBP), diastolic blood pressure (DBP); blood lipids: low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG); thyroid function: hyperthyroidism, hypothyroidism; body mass index (BMI), waist-hip-ratio (WHR), and insulin sensitivity.Main outcomesCardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke.MethodsSummary-level data for exposures and main outcomes were extracted from GWAS consortia. We used two-sample MR to illustrate the causal effect of T2DM on CVD subtypes and regression-based MVMR to quantify the possible mediation effects of cardiometabolic factors on CVD.ResultsEach additional unit of log odds of T2DM increased 16% risk of CHD [odds ratio (OR): 1.16, 95% CI: 1.12-1.21], 15% risk of myocardial infarction (MI) (OR: 1.15, 95% CI: 1.10-1.20), and 10% risk of stroke (OR: 1.10, 95% CI: 1.06-1.13). In mediation analysis, SBP, DBP, and TG were found as main mediators, while the mediation effects of other cardiometabolic factors were not significant. The proportion of total effect of T2DM on CHD mediated by SBP, DBP, and TG was 16% (95% CI: 8-24%), 7% (95% CI: 1-13%) and 10% (95% CI: 2-18%), respectively. Mediation effect of SBP and DBP on MI and stroke, TG on MI was also prominent, while mediation effect of TG on stroke was not significant. The combined mediation effect of all the three mediators accounted for 29%, 26%, and 13% of the total effect of T2DM on CHD, MI, and stroke, respectively.ConclusionSystolic blood pressure, DBP, and TG mediate a substantial proportion of the causal effect of T2DM on CVD and thus interventions on these factors might reduce the considerable excess risk of CVD among patients with T2DM.
| S-EPMC8909643 | biostudies-literature
Project description:A Mendelian randomization (MR) study was undertaken to establish a causal link between gastroesophageal reflux disease (GERD) and frozen shoulder (FS), examining whether the risk of GERD with FS is mediated through mood fluctuations. Genetic loci from populations of independent European ancestry were selected as instrumental variables for GERD, FS, and mood swings. The primary analysis employed the inverse-variance weighted method supplemented by 3 additional analytical methods. This was conducted using two-sample and two-step MR analyses. This study explored the correlation and mediating effects of mood swings between GERD and FS. Our study employed heterogeneity and horizontal diversity, and sensitivity analysis was conducted using the leave-one-out method to explore the robustness of the results. In the two-sample MR analysis, for every 1-unit increase in the log-transformed odds ratio (OR) of GERD, the corresponding OR increased to 1.844 (inverse-variance weighting: OR = 1.844, 95% confidence interval: 1.47-2.30, P < .001). In the two-step MR analysis, we found that mood swings played a mediating role in the association between GERD and FS. We assessed this mediating effect using the delta method (b = 0.181, SE = 0.059, OR = 1.199, 95% confidence interval: 1.072-1.349). Analysis of the data using the above methods indicated that GERD is a risk factor for FS, and mood swings mediate between the 2. Therefore, GERD and mood swings should be included in the health management of patients with FS.
| S-EPMC11537667 | biostudies-literature