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. 2024 Jul 4:15:1378645.
doi: 10.3389/fendo.2024.1378645. eCollection 2024.

Causal impact of human blood metabolites and metabolic pathways on serum uric acid and gout: a mendelian randomization study

Yan Zhong  1 , ChengAn Yang  1 , BingHua Zhang  1 , YingWen Chen  2 , WenJun Cai  3 , GuoChen Wang  1 , ChangWei Zhao  4 , WenHai Zhao  4
Affiliations

Causal impact of human blood metabolites and metabolic pathways on serum uric acid and gout: a mendelian randomization study

Yan Zhong et al. Front Endocrinol (Lausanne). .

Abstract

Objective: Hyperuricaemia and gout are common metabolic disorders. However, the causal relationships between blood metabolites and serum urate levels, as well as gout, remain unclear. A systematic evaluation of the causal connections between blood metabolites, hyperuricemia, and gout could enhance early screening and prevention of hyperuricemia and gout in clinical settings, providing novel insights and approaches for clinical treatment.

Methods: In this study, we employed a bidirectional two-sample Mendelian randomization analysis utilizing data from a genome-wide association study involving 7,286 participants, encompassing 486 blood metabolites. Serum urate and gout data were sourced from the Chronic Kidney Disease Genetics consortium, including 288,649 participants for serum urate and 9,819 African American and 753,994 European individuals for gout. Initially, LDSC methodology was applied to identify blood metabolites with a genetic relationship to serum urate and gout. Subsequently, inverse-variance weighting was employed as the primary analysis method, with a series of sensitivity and pleiotropy analyses conducted to assess the robustness of the results.

Results: Following LDSC, 133 blood metabolites exhibited a potential genetic relationship with serum urate and gout. In the primary Mendelian randomization analysis using inverse-variance weighting, 19 blood metabolites were recognized as potentially influencing serum urate levels and gout. Subsequently, the IVW p-values of potential metabolites were corrected using the false discovery rate method. We find leucine (IVW P FDR = 0.00004), N-acetylornithine (IVW P FDR = 0.0295), N1-methyl-3-pyridone-4-carboxamide (IVW P FDR = 0.0295), and succinyl carnitine (IVW P FDR = 0.00004) were identified as significant risk factors for elevated serum urate levels. Additionally, 1-oleoylglycerol (IVW P FDR = 0.0007) may lead to a substantial increase in the risk of gout. Succinyl carnitine exhibited acceptable weak heterogeneity, and the results for other blood metabolites remained robust after sensitivity, heterogeneity, and pleiotropy testing. We conducted an enrichment analysis on potential blood metabolites, followed by a metabolic pathway analysis revealing four pathways associated with serum urate levels.

Conclusion: The identified causal relationships between these metabolites and serum urate and gout offer a novel perspective, providing new mechanistic insights into serum urate levels and gout.

Keywords: Mendelian randomization; blood metabolite; gout; hyperuricemia; risk factor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mendelian randomization research process.
Figure 2
Figure 2
Known Blood metabolites Showing a Significant Relationship with SU After FDR. CI, confidence interval; Beta(95%CI), 95% confidence interval for beta; PDR, P-value for error rate correction.
Figure 3
Figure 3
Known Blood metabolites Showing a Significant Relationship with gout After FDR Correctiontics for IVW. Correction. OR, odds ratio; OR (95%CI), 95% confidence interval for OR.
Figure 4
Figure 4
Relationship between serum urate and known blood metabolites after correction for FDR.
Figure 5
Figure 5
Relationship between gout and known blood metabolites after correction for FDR.
Figure 6
Figure 6
Metabolite KEGG enrichment analysis.
See this image and copyright information in PMC

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