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Serum Albumin and Circulating Metabolites and Risk of Venous Thromboembolism: A Two-Sample Mendelian Randomization Study.

ABSTRACT: Background and Aim: Previous observational studies indicated that the serum albumin levels and circulating metabolites are associated with a high risk of venous thromboembolism (VTE). However, whether these observations reflect causality remained unclear. Hence, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal associations of serum albumin and circulating metabolites with the risk of VTE. Methods and Results: Summary statistics of genetic instruments proxying serum albumin, total protein, and common circulating metabolites were extracted from genome-wide association studies in the European ancestry. Summary-level results of age- and sex-adjusted estimates for associations of the instruments with VTE were derived from the FinnGen consortium. We used the inverse-variance weighted (IVW) method as the primary analysis for univariable MR. Sensitivity analyses were performed to detect horizontal pleiotropy and outliers. Genetically proxied high-serum albumin and total protein levels were suggestive protective factor of VTE, with odds ratio (OR) = 0.69 (CI 0.54-0.89, p = 4.7 × 10^-3) and 0.76 (CI 0.61-0.95, p = 0.015), respectively. Genetically proxied low-monounsaturated fatty acids and the ratio of monounsaturated fatty acid to total fatty acid are causally associated with increased risk of VTE, with ORs = 0.89 (CI 0.80-0.99, p = 0.031) and 0.85 (CI 0.78-0.94, p = 9.92 × 10^-4), respectively. There is no indication of causal associations between other circulating metabolites and the risk of VTE. Conclusions: Genetically liability to low-serum albumin and total protein levels, low proxied monounsaturated fatty acids (MUFAs) and the ratio of MUFAs to total fatty acids are associated with the higher risk of VTE.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8631825 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo investigate the genetic underpinnings of the association between type 2 diabetes (T2D), glycemic indicators such as fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (GH), and venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), thereby contributing novel insights to the scholarly discourse within this domain.MethodsGenome-wide association study (GWAS) summary data pertaining to exposures (T2D, FG, FI, GH) and outcomes (VTE, DVT, PE) were acquired from the IEU Open GWAS database, encompassing participants of European descent, including both male and female individuals. Two-sample Mendelian randomization (MR) analyses were conducted utilizing the TwoSampleMR and MRPRESSO packages within the R programming environment. The primary analytical approach employed was the random-effects inverse variance weighted (IVW) method. Heterogeneity was assessed via Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger. Horizontal pleiotropy was evaluated using the intercept test of MR Egger and MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, with the latter also employed for outlier detection. Additionally, a "Leave one out" analysis was conducted to ascertain the influence of individual single nucleotide polymorphisms (SNPs) on MR results.ResultsThe random-effects IVW analysis revealed a negative genetic causal association between T2D) and VTE (P = 0.008, Odds Ratio [OR] 95% confidence interval [CI] = 0.896 [0.827-0.972]), as well as between FG and VTE (P = 0.002, OR 95% CI = 0.655 [0.503-0.853]), GH and VTE (P = 0.010, OR 95% CI = 0.604 [0.412-0.884]), and GH and DVT (P = 0.002, OR 95% CI = 0.413 [0.235-0.725]). Conversely, the random-effects IVW analysis did not detect a genetic causal relationship between FI and VTE (P > 0.05), nor between T2D, FG, or FI and DVT (P > 0.05), or between T2D, FG, FI, or GH and PE (P > 0.05). Both the Cochran's Q statistic for MR-IVW and Rucker's Q statistic for MR-Egger indicated no significant heterogeneity (P > 0.05). Moreover, the intercept tests of MR Egger and MR-PRESSO suggested the absence of horizontal pleiotropy (P > 0.05). MR-PRESSO analysis identified no outliers, while the "Leave one out" analysis underscored that the MR analysis was not influenced by any single SNP.ConclusionOur investigation revealed that T2D, FG, and GH exhibit negative genetic causal relationships with VTE at the genetic level, while GH demonstrates a negative genetic causal relationship with DVT at the genetic level. These findings furnish genetic-level evidence warranting further examination of VTE, DVT, and PE, thereby making a contribution to the advancement of related research domains.

Project description:BackgroundEmerging evidence indicates a correlation between imbalances in intestinal microbiota and changes in plasma metabolites in the progression of asthma. However, the causal link between these factors remains unclear.MethodsA two-sample Mendelian randomization (MR) study was employed to evaluate the potential causal connection between gut microbiota, plasma metabolites, and asthma susceptibility. Gut microbiota data from expansive genome-wide genotype studies and 16S fecal microbiome datasets were examined by the MiBioGen Alliance. Asthma data were procured from the FinnGen biobank analysis, while comprehensive Genome-Wide Association Studies (GWAS) summary statistics for plasma metabolites were derived from the NHGRI-EBI GWAS Catalog. Fluctuations in intestinal flora and plasma metabolites in asthma patients were evaluated using the weighted mode method. Additionally, pleiotropic and heterogeneity analyses were performed to ascertain the reliability of the findings.ResultsUpon examining the gut microbiota through MR with the IVW method, alongside tests for heterogeneity and pleiotropy, findings reveal a negative association between the abundance of the Christensenellaceae R.7 group and asthma risk. In contrast, the Bifidobacterium and Prevotella 7 genera exhibit a positive association with asthma risk, indicating they may be potential risk factors (p < 0.05). Furthermore, MR analysis of 1,400 metabolites employing Weighted median, IVW, and Weighted mode methods resulted in p-values below 0.05. Subsequent tests for pleiotropy and heterogeneity showed that the levels of 3,5-dichloro-2,6-dihydroxybenzoic acid have a negative correlation with asthma, whereas the phenylalanine to phosphate ratio has a positive correlation, suggesting their potential as risk factors for asthma (p < 0.05).ConclusionThe current Mendelian randomization study provides evidence supporting a potential causal link between specific gut microbiota taxa, plasma metabolites, and asthma. These findings offer novel perspectives for future research and the development of treatment and prevention strategies for asthma.

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Serum Albumin and Circulating Metabolites and Risk of Venous Thromboembolism: A Two-Sample Mendelian Randomization Study.

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