The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study
Ontology highlight
ABSTRACT:
SUBMITTER: Pan T
PROVIDER: S-EPMC11020755 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background/Aim: Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis. Methods: Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy. Results: Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13-1.29, p = 3.16 × 10-4), ferritin (OR = 1.32, 95%CI = 1.07-1.62, p =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06-1.23, p = 5.43 × 10-4) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed. Conclusions: This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.
| S-EPMC8639868 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is an irreversible lung disease with unclear pathological mechanisms. In this study, we utilized bidirectional Mendelian randomization (MR) to analyze the relationship between serum metabolites and IPF, and conducted metabolic pathway analysis.AimTo determine the causal relationship between serum metabolites and IPF using MR analysis.MethodsA two-sample MR analysis was conducted to evaluate the causal relationship between 824 serum metabolites and IPF. The inverse variance weighted (IVW) method was used to estimate the causal relationship between exposure and results. Sensitivity analysis was conducted using MR Egger, weighted median, and maximum likelihood to eliminate pleiotropy. Additionally, metabolic pathway analysis was conducted to identify potential metabolic pathways.ResultsWe identified 12 serum metabolites (6 risks and 6 protective) associated with IPF from 824 metabolites. Among them, 11 were known and 1 was unknown. 1-Eicosatrienoylglycophorophospholine and 1-myristoylglycophorophospholine were bidirectional MR positive factors, with 1-myristoylglycophorophospholine being a risk factor (1.0013, 1.0097) and 1-eicosatrienoylglycophorine being a protective factor (0.9914, 0.9990). The four lipids (1-linoleoylglycerophoethanolamine*, total cholesterol in large high-density lipoprotein [HDL], cholesterol esters in very large HDL, and phospholipids in very large HDL) and one NA metabolite (degree of unsaturation) were included in the known hazardous metabolites. The known protective metabolites included three types of lipids (carnitine, 1-linoleoylglycerophoethanolamine*, and 1-eicosatrienoylglycerophophophorine), one amino acid (hypoxanthine), and two unknown metabolites (the ratio of omega-6 fatty acids to omega-3 fatty acids, and the ratio of photoshopids to total lipids ratio in chylomicrons and extremely large very low-density lipoprotein [VLDL]). Moreover, sn-Glycerol 3-phosphate and 1-Acyl-sn-glycero-3-phosphocline were found to be involved in the pathogenesis of IPF through metabolic pathways such as Glycerolide metabolism and Glycerophospholipid metabolism.ConclusionOur study identified 6 causal risks and 6 protective serum metabolites associated with IPF. Additionally, 2 metabolites were found to be involved in the pathogenesis of IPF through metabolic pathways, providing a new perspective for further understanding the metabolic pathway and the pathogenesis of IPF.
| S-EPMC11369467 | biostudies-literature
Project description:BackgroundEvidence from numerous observational studies and clinical trials has linked gut microbiota and metabolites to digestive tract cancer. However, the causal effect between these factors remains uncertain.MethodsData for this study were obtained from the MiBioGen, TwinsUK Registry, and FinnGen (version R8). Two-sample Mendelian randomization analysis with inverse variance weighting method was primarily used, and the results were validated by heterogeneity analysis, pleiotropy test, and sensitivity analysis.ResultsAt P < 5 × 10-8, our analysis identified four gut microbiotas as risk factors for digestive tract cancer and six as risk factors for colorectal cancer. Conversely, one gut microbiota exhibited protection against bile duct cancer, and two showed protective effects against stomach cancer. At P < 1 × 10-5, our investigation revealed five, six, three, eight, eight, and eight gut microbiotas as risk factors for esophageal, stomach, bile duct, liver, pancreatic, and colorectal cancers, respectively. In contrast, four, two, eight, two, two, and five gut microbiotas exhibited protective effects against these cancers. Additionally, GABA, a metabolite of gut microbiota, displayed a significant protective effect against colorectal cancer.ConclusionIn conclusion, specific gut microbiota and metabolites play roles as risk factors or protective factors for digestive tract cancer, and a causal relationship between them has been established, offering novel insights into gut microbiota-mediated cancer development.
| S-EPMC10681779 | biostudies-literature
Project description:BackgroundIn observational studies, frailty has been strongly associated with mental disorders. However, the mechanisms underlying the association between frailty and mental disorders remain unclear.MethodsWe conducted a two-sample Mendelian randomization (MR) study to assess the causal relationship between frailty, as measured by the frailty index (FI), and ten common mental disorders. The datasets involved European ancestry individuals and included measurements of the FI (N = 175,226), schizophrenia (SCZ; N = 320,404), major depressive disorder (MDD; N = 143,265), bipolar disorder (N = 337,199), insomnia (N = 462,341), obsessive-compulsive disorder (N = 33,925), anxiety disorders (N = 463,010), autism spectrum disorder (N = 46,351), anorexia nervosa (N = 14,477), opioid-related mental and behavioral disorders (N = 215,650), and mental and behavioral disorders due to use of other stimulants including caffeine (N = 215,570).ResultsTwo-sample MR analyses were performed using inverse variance weighting followed by various sensitivity and validation analyses. Genetically predicted SCZ (odds ratio [OR] = 1.019, 95% confidence interval [CI] 1.005-1.033) and MDD (OR = 1.211, 95% CI 1.092-1.343) had significant causal effects on FI. In the reverse MR analysis, we discovered that MDD was significantly and causally affected by FI (OR = 1.290, 95% CI 1.133-1.469). No causal links were identified between the FI and the other eight common mental disorders. In the Multivariable MR, the estimated MDD effect on FI is comparable to the univariate IVW estimate (OR = 1.298; 95% CI, 1.175 to 1.435), while the estimated SCZ effect on FI fails to be significant compared to the univariate estimate. The results of the sensitivity and validation analyses confirmed stabilization.ConclusionsOur study found evidence of a causal relationship between SCZ, MDD, and frailty and explored the underlying mechanisms.
| S-EPMC11665248 | biostudies-literature
Project description:BackgroundRecent studies have increasingly emphasized the strong correlation between the lipidome and the risk of pancreatic diseases. To determine causality, a Mendelian randomization (MR) analysis was performed to identify connections between the lipidome and pancreatic diseases.MethodsStatistics from a genome-wide association study of the plasma lipidome, which included a diverse array of 179 lipid species, were obtained from the GeneRISK cohort study with 7,174 participants. Genetic associations with four types of pancreatitis and pancreatic cancer were sourced from the R11 release of the FinnGen consortium. Two pancreatitis datasets from UK Biobank were employed as the validation cohort. MR analysis was conducted to assess the relationship between the genetically predicted plasma lipidome and these pancreatic diseases. Inverse variance weighted was adopted as the main statistical method. Bayesian weighted MR was employed for further verification. The MR-Egger intercept test for pleiotropy and Cochrane's Q statistics test for heterogeneity were performed to ensure the robustness.ResultsMR analysis yielded significant evidence that 26, 25, 2, and 19 lipid species were correlated with diverse outcomes of pancreatitis, and 8 lipid species were correlated with pancreatic cancer. Notably, sterol ester (27:1/20:2) levels (OR: 0.84, 95% CI: 0.78-0.90, P = 5.79 × 10-7) were significantly associated with acute pancreatitis, and phosphatidylcholine (17:0_20:4) levels (OR: 0.89, 95% CI: 0.84-0.94, P = 1.78 × 10-4) and sterol ester (27:1/20:4) levels (OR: 0.90, 95% CI: 0.86-0.95, P = 2.71 × 10-4) levels were significantly associated with chronic pancreatitis after the Bonferroni-corrected test. As for validation, 14 and 9 lipid species were correlated with acute and chronic pancreatitis of UK Biobank. Some lipid classes showed significant effects both in the FinnGen consortium and UK Biobank datasets.ConclusionsThe findings of this study indicate a potential genetic predisposition linking the plasma lipidome to pancreatic diseases and good prospects for future pancreatic disease clinical trials.
| S-EPMC11774697 | biostudies-literature
Project description:This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer (odds ratio [OR] 0.95; 95% CI 0.90-0.99, p = 0.02). Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type (OR 0.91; 95% CI 0.86-0.97, p = 0.005). However, there was no causal association between ER-negative breast cancer and survival (OR 1.00; 95% CI 0.94-1.06, p = 0.89). Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association.
| S-EPMC10570324 | biostudies-literature
Project description:Objectives: Although it has long been reported that high levels of cystatin C could contribute to the development of osteoporosis in some studies, no evidence has established a causal association between them thus far. Methods: A Mendelian randomization (MR) study was conducted to determine the causal effect of cystatin C on osteoporosis based on public databases obtained from separately published genome-wide association studies (GWASs). The single-nucleotide polymorphisms (SNPs) for cystatin C were extracted from the MR-Base (CKDGen, 33,152 participants), and the SNPs for osteoporosis were extracted from the United Kingdom Biobank project (United Kingdom Biobank, including 5,266 osteoporosis cases and 331,893 controls). We defined the odds ratio (OR) of IVW methods as the primary outcome. In addition, weighted median and MR-Egger regressions were used in the sensitivity analysis. Results: In IVW, we found that genetically predicted cystatin C was causally associated with the risk of osteoporosis with an OR of 1.02 [95% confidence interval (CI) = 1.003-1.025, p = 0.01]. In the further sensitivity analysis, weighted median regression also showed directionally similar estimates (OR = 1.02, 95% CI = 1.005-1.03, p = 0.005), and MR-Egger regression (OR = 1.02, 95% CI = 1.000-1.036, p = 0.15) revealed similar estimates but with lower precision. The funnel plot, MR-Egger intercept, and MR-PRESSO all indicate that no directional pleiotropic effect was observed. Conclusion: In conclusion, our MR study showed evidence of a causal association between serum cystatin C levels and osteoporosis, which also needs to be verified by studies with larger sample sizes in the future. Early monitoring of cystatin C may enable us to prevent osteoporosis-related diseases.
| S-EPMC9136661 | biostudies-literature
Project description:BackgroundRecent research linked changes in the gut microbiota and serum metabolite concentrations to intracerebral hemorrhage (ICH). However, the potential causal relationship remained unclear. Therefore, the current study aims to estimate the effects of genetically predicted causality between gut microbiota, serum metabolites, and ICH.MethodsSummary data from genome-wide association studies (GWAS) of gut microbiota, serum metabolites, and ICH were obtained separately. Gut microbiota GWAS (N = 18,340) were acquired from the MiBioGen study, serum metabolites GWAS (N = 7,824) from the TwinsUK and KORA studies, and GWAS summary-level data for ICH from the FinnGen R9 (ICH, 3,749 cases; 339,914 controls). A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects between gut microbiota, serum metabolites, and ICH. The random-effects inverse variance-weighted (IVW) MR analyses were performed as the primary results, together with a series of sensitivity analyses to assess the robustness of the results. Besides, a reverse MR was conducted to evaluate the possibility of reverse causation. To validate the relevant findings, we further selected data from the UK Biobank for analysis.ResultsMR analysis results revealed a nominal association (p < 0.05) between 17 gut microbial taxa, 31 serum metabolites, and ICH. Among gut microbiota, the higher level of genus Eubacterium xylanophilum (odds ratio (OR): 1.327, 95% confidence interval (CI):1.154-1.526; Bonferroni-corrected p = 7.28 × 10-5) retained a strong causal relationship with a higher risk of ICH after the Bonferroni corrected test. Concurrently, the genus Senegalimassilia (OR: 0.843, 95% CI: 0.778-0.915; Bonferroni-corrected p = 4.10 × 10-5) was associated with lower ICH risk. Moreover, after Bonferroni correction, only two serum metabolites remained out of the initial 31 serum metabolites. One of the serum metabolites, Isovalerate (OR: 7.130, 95% CI: 2.648-19.199; Bonferroni-corrected p = 1.01 × 10-4) showed a very strong causal relationship with a higher risk of ICH, whereas the other metabolite was unidentified and excluded from further analysis. Various sensitivity analyses yielded similar results, with no heterogeneity or directional pleiotropy observed.ConclusionThis two-sample MR study revealed the significant influence of gut microbiota and serum metabolites on the risk of ICH. The specific bacterial taxa and metabolites engaged in ICH development were identified. Further research is required in the future to delve deeper into the mechanisms behind these findings.
| S-EPMC10829105 | biostudies-literature
Project description:BackgroundDilated cardiomyopathy (DCM) is a cardiac disease with a poor prognosis of unclear etiology. Previous studies have shown that metabolism is associated with DCM. This study investigates the causal relationship between 1400 metabolites and DCM using a two-sample Mendelian randomization (MR) approach.MethodsThe study utilized data from the OpenGWAS database, comprising 355,381 Europeans, including 1,444 DCM cases. A total of 1,400 metabolites were evaluated for their causal association with DCM. Instrumental variables (IVs) were selected based on genetic variation and used in the MR analysis. The primary analysis method was inverse variance weighting (IVW), supplemented by weighted median-based estimation and sensitivity analyses.ResultsOf the 1,400 metabolites analyzed, 52 were identified as causally associated with DCM. The analysis revealed both positively and negatively correlated metabolites with DCM risk. Notable findings include the positive correlation of Tryptophan betaine and 5-methyluridine (ribothymidine) levels, and an inverse association of Myristoleate and Erythronate levels with DCM.ConclusionsThe study provides significant insights into the metabolites potentially involved in the pathogenesis of DCM. These findings could pave the way for new therapeutic strategies and biomarker identification in DCM management.
| S-EPMC11424463 | biostudies-literature
Project description:To explore the causal relationship between gut microbiota (GM) and Idiopathic pulmonary fibrosis (IPF), we performed a two-sample Mendelian randomization (MR). GM was used as an exposure factor, and instrumental variables were determined from the GWAS of 18,340 participants. GWAS of IPF (including 1028 IPF patients and 196,986 controls) from the FinnGen was used as the outcome factor. The primary analysis method is the inverse variance weighted (IVW) method, and sensitivity analysis was used to validate the reliability. Family Bacteroidaceae (OR = 1.917 95% CI = 1.083-3.393, P = .026), order Gastranaerophilales (OR = 1.441 95% CI = 1.019-2.036, P = .039), genus Senegalimassilia (OR = 2.28 95% CI = 1.174-4.427, P = .015), phylum Cyanobacteria (OR = 1.631 95% CI = 1.035-2.571, P = .035) were positively correlated with IPF. FamilyXIII(OR = 0.452 95% CI = 0.249-0.82, P = .009), order Selenomonadale (OR = 0.563 95% CI = 0.337-0.941, P = .029), genus Veillonella (OR = 0.546 95% CI = 0.304-0.982, P = .043) (OR = 0.717 95% CI = 0.527-0.976, P = .034), genus Ruminococcusgnavus (OR = 0.717 95% CI = 0.527-0.976, P = .034), genus Oscillibacter (OR = 0.571 95% CI = 0.405-0.806, P = .001) was negatively correlated with IPF. Sensitivity analysis showed no evidence of pleiotropy or heterogeneity (P > .05). The results of MR demonstrated a causal relationship between GM and IPF. Further studies are needed to investigate the intrinsic mechanisms of the GM in the pathogenesis of IPF.
| S-EPMC11398756 | biostudies-literature