Dataset Information

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

ABSTRACT:

Background

Urolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood.

Method

In our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary approach, complemented by several other estimators including MR-Egger, weighted median, colocalization and MR-PRESSO. Furthermore, the study included replication and meta-analysis. Finally, we conducted metabolic pathway analysis to elucidate potential metabolic pathways.

Results

After conducting multiple tests for correction, glycerol might contribute to the urolithiasis and dehydroisoandrosterone sulfate (DHEA-S) might inhibit this process. Furthermore, several blood metabolites had shown potential associations with a causal relationship. Among the protective metabolites were lipids (dehydroisoandrosterone sulfate and 1-stearoylglycerol (1-monostearin)), amino acids (isobutyrylcarnitine and 2-aminobutyrate), a keto acid (acetoacetate) and a carbohydrate (mannose). The risk metabolites included lipids (1-palmitoylglycerophosphoethanolamine, glycerol and cortisone), a carbohydrate (erythronate), a peptide (pro-hydroxy-pro) and a fatty acid (eicosenoate). In reverse MR analysis, urolithiasis demonstrated a statistically significant causal relationship with butyrylcarnitine, 3-methyl-2-oxobutyrate, scyllo-inositol, leucylleucine and leucylalanine. However, it was worth noting that none of the blood metabolites exhibited statistical significance after multiple corrections. Additionally, we identified one metabolic pathway associated with urolithiasis.

Conclusion

The results we obtained demonstrate the causal relevance between two metabolites and urolithiasis, as well as identify one metabolic pathway potentially associated with its development. Given the high prevalence of urolithiasis, further investigations are encouraged to elucidate the mechanisms of these metabolites and explore novel therapeutic strategies.

SUBMITTER: Hu D

PROVIDER: S-EPMC11350957 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

Hu Dekai D Pan Jiashan J Deng Anqi A Ge Defeng D Yao Rui R Hou Bingbing B Hao Zongyao Z

BMC urology 20240828 1

<h4>Background</h4>Urolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood.<h4>Method</h4>In our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary appro ...[more]

PMID: 39198784

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Project description:BackgroundUrolithiasis is a prevalent condition encountered in urology. Over the past decade, its global incidence has been on an upward trajectory; paired with a high recurrence rate, this presents considerable health and economic burdens. Although inflammatory factors are pivotal in the onset and progression of urolithiasis, their causal linkages remain elusive.MethodMendelian randomization (MR) is predicated upon genome-wide association studies (GWASs). It integrates bioinformatics analyses to reveal causal relationships between exposures and outcomes, rendering it an effective method with minimized bias. Drawing from a publicly accessible GWAS meta-analysis comprising 8,293 samples, we identified 41 genetic variations associated with inflammatory cytokines as instrumental variables. Outcome data on upper urinary tract stones, which included renal and ureteral stones (9,713 cases and 366,693 controls), and lower urinary tract stones, including bladder and urethral stones (1,398 cases and 366,693 controls), were derived from the FinnGen Consortium R9 dataset. By leveraging the bidirectional MR methodology, we aimed to decipher the causal interplay between inflammatory markers and urolithiasis.ResultsOur study comprehensively elucidated the association between genetic inflammatory markers and urolithiasis via bidirectional Mendelian randomization. Post-MR analysis of the 41 genetic inflammation markers revealed that elevated levels of circulating interleukin-2 (IL-2) (OR = 0.921, 95% CI = 0.848-0.999) suggest a reduced risk for renal stone disease, while heightened stem cell growth factor beta (SCGF-β) (OR = 1.150, 95% CI = 1.009-1.310) and diminished macrophage inflammatory protein 1 beta (MIP-1β) (OR = 0.863, 95% CI = 0.779-0.956) levels suggest an augmented risk for lower urinary tract stones. Furthermore, renal stone disease appeared to elevate IL-2 (β = 0.145, 95% CI = 0.013-0.276) and cutaneous T cell-attracting chemokine (CTACK) (β = 0.145, 95% CI = 0.013-0.276) levels in the bloodstream, whereas lower urinary tract stones were linked to a surge in interleukin-5 (IL-5) (β = 0.142, 95% CI = 0.057-0.226), interleukin-7 (IL-7) (β = 0.108, 95% CI = 0.024-0.192), interleukin-8 (IL-8) (β = 0.127, 95% CI = 0.044-0.210), growth regulated oncogene alpha (GRO-α) (β = 0.086, 95% CI = 0.004-0.169), monokine induced by interferon-gamma (MIG) (β = 0.099, 95% CI = 0.008-0.191) and macrophage inflammatory protein 1 alpha (MIP-1α) (β = 0.126, 95% CI = 0.044-0.208) levels.ConclusionThese discoveries intimate the instrumental role of IL-2 in the onset and progression of upper urinary tract stones. SCGF-β and MIP-1β influence the development of lower urinary tract stones. Urolithiasis also impacts the expression of cytokines such as IL-2, CTACK, IL-5, IL-7, IL-8, GRO-α, MIG, and MIP-1α. There is a pressing need for further investigation to ascertain whether these biomarkers can be harnessed to prevent or treat urolithiasis.

Project description:BackgroundUrolithiasis is a common urological disease with increasing incidence worldwide, and preventing its risk poses significant challenges. Here, we used Mendelian randomization (MR) framework to genetically assess the causal nature of multifaceted risk factors on urolithiasis.Methods17 potential risk factors associated with urolithiasis were collected from recently published observational studies, which can be categorized basically into lifestyle factors and circulating biomarkers. The instrumental variables of risk factors were selected from large-scale genome-wide association studies (N ≤ 607,291). Summary-level data on urolithiasis were obtained from UK Biobank (UKB) (3,625 cases and 459,308 noncases) and the FinnGen consortium (5,347 cases and 213,445 noncases). The univariable and multivariable MR analyses were applied to evaluate the causal, independent effect of these potential risk factors upon urolithiasis. Effects from the two consortia were combined by the meta-analysis methods.ResultsHigher genetically predicted sex hormone-binding globulin (SHBG, OR, 0.708; 95% CI, 0.555 to 0.903), estradiol (OR, 0.179; 95% CI, 0.042 to 0.751), tea intake (OR, 0.550; 95% CI, 0.345 to 0.878), alcoholic drinks per week (OR, 0.992; 95% CI, 0.987 to 0.997), and some physical activity (e.g., swimming, cycling, keeping fit, and bowling, OR, 0.054; 95% CI, 0.008 to 0.363) were significantly associated with a lower risk of urolithiasis. In the Multivariate Mendelian Randomization (MVMR) analyses, the significant causal associations between estradiol, SHBG, tea intake, and alcoholic drinks per week with urolithiasis were robust even after adjusting for potential confounding variables. However, the previously observed causal association between other exercises and urolithiasis was no longer significant after adjusting for these factors.ConclusionsThe univariable and multivariable MR findings highlight the independent and significant roles of estradiol, SHBG, tea intake, and alcoholic drinks per week in the development of urolithiasis, which might provide a deeper insight into urolithiasis risk factors and supply potential preventative strategies.

Project description:BackgroundLung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear.MethodsThis study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses.ResultsThe MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.).ConclusionThis study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.

Project description:Background and aimsAutism spectrum disorder (ASD) is a complex neurodevelopmental condition with a poorly understood etiology. Recent studies have suggested that metabolic dysregulation might be linked to the development of ASD; however, causal relationships remain unclear. This study aimed to investigate the causal association between these factors using two-sample Mendelian randomization (TSMR).MethodsWe conducted a TSMR analysis to assess the relationship between blood metabolites and ASD using summarized GWAS data. The metabolite dataset from the Canadian Longitudinal Study of Aging included 1091 metabolites and 309 ratios from 7824 European individuals. The ASD data from the Psychiatric Genomics Consortium comprised 18,381 ASD cases and 27,969 controls. Blood metabolites were set as exposures with ASD as the outcome. We primarily used the inverse-variance weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We also conducted sensitivity analyses to confirm robustness. Replication, confounding, and reserve analyses were performed to verify causation. Additionally, metabolic pathway and network pharmacology analyses were conducted to explore potential mechanisms.ResultsWe identified 55 known metabolites including 13 metabolite ratios and 10 unknown blood metabolites associated with ASD. Additionally, our analysis identified 13 potential metabolic pathways, among which tryptophan metabolism was the most notable (p = 0.0388). Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes analysis highlighted crucial pathways, such as cellular glucuronidation, glucuronosyltransferase activity, and bile secretion, and the significance of the apical part of the cell.ConclusionsOur findings indicate that the dodecenedioate, methionine sulfone, cysteine to alanine ratio and proline to glutamate ratio have an impact on ASD. These results enhance our understanding of the metabolic pathways involved in ASD and could lead to new avenues for intervention and prevention. Further research is needed to explore the mechanisms underlying these associations and confirm these findings in different populations.

Project description:BackgroundPeripheral Artery Disease (PAD) is a common vascular disorder typically caused by atherosclerosis, leading to impaired blood supply to the lower extremities, resulting in pain, necrosis, and even amputation. Despite extensive research into the pathogenesis of PAD, many mysteries remain, particularly regarding its association with human blood metabolites.MethodsTo explore the causal relationship between 1,400 serum metabolites and PAD, a two-sample Mendelian randomization (MR) analysis was conducted. The Inverse Variance-Weighted (IVW) method was the primary technique used to estimate the causal impact of the metabolites on PAD. To enhance the analysis, several additional methods were employed: MR-Egger regression, weighted median, simple mode, and weighted mode. These methods provided a comprehensive evaluation beyond the primary IVW estimation. To ensure the validity of the MR findings, sensitivity analysis was performed. Furthermore, a bidirectional MR approach was applied to explore the possibility of a reverse causal effect between PAD and potential candidate metabolites.ResultsAfter rigorous selection, significant associations were found between 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 levels with PAD. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) was positively associated with increased PAD risk (IVW OR = 1.13, 95% CI, 1.06-1.21; P < 0.001). X-17653 levels were associated with decreased PAD risk (IVW OR = 0.88, 95% CI, 0.83-0.94; P < 0.001). In the reverse direction, PAD was positively associated with increased 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) levels (IVW OR = 1.16, 95% CI, 1.01-1.34; P = 0.036). PAD was not associated with X-17653.ConclusionAmong 1,400 blood metabolites, 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 are signiﬁcantly associated with PAD risk. Importantly, in the reverse direction, PAD was found to be positively associated with increased levels of 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4). This highlights the bidirectional nature of the association and suggests a potential feedback mechanism between PAD and this specific lipid species. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) may serve as potential biomarkers for PAD, aiding early diagnosis and providing novel avenues for personalized treatment and management. However, further validation and research are warranted despite the promising results.

Dataset Information

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

Background

Method

Results

Conclusion

Publications

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

Similar Datasets

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