Xuanshuo Liu, Bohua Chen, Jianghao Yuan, Shuhao Li, Lei Gao, Mingyan Chu, Shicang Fan, Weiwei Fan
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The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions.</p><p><strong>Methods: </strong>This study integrates genome-wide association study (GWAS) summary statistics for RM from the FinnGen database, data on crotonylation-associated gene expression obtained from the eQTLGen consortium, and metabolite GWAS data obtained from the GWAS Catalog. A combined two-sample Mendelian randomization (MR), summary data-based Mendelian randomization (SMR), and mediation analyses were performed to investigate the causal link between Glutaryl-CoA dehydrogenase (GCDH) and RM, with a specific focus on glutarylcarnitine metabolism.</p><p><strong>Results: </strong>MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, P = 0.0045). Mediation analysis revealed that elevated GCDH expression significantly reduced glutarylcarnitine (C5-DC) levels, which in turn was inversely associated with RM risk. A three-step MR-based mediation confirmed a significant mediating effect of glutarylcarnitine (β₁₂ = 0.0680, P = 0.002), with 30.25% of the total effect attributable to it. The robustness of these findings was further demonstrated by sensitivity analyses and SMR results.</p><p><strong>Conclusion: </strong>This study represents the first evidence that GCDH might exert an indirect pro-RM effect via the downregulation of glutarylcarnitine, thus providing new insights into tumor metabolic pathways and positioning glutarylcarnitine as a potentially diagnostic biomarker and therapeutic target for RM.</p>","PeriodicalId":11148,"journal":{"name":"Discover. 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The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions.</p><p><strong>Methods: </strong>This study integrates genome-wide association study (GWAS) summary statistics for RM from the FinnGen database, data on crotonylation-associated gene expression obtained from the eQTLGen consortium, and metabolite GWAS data obtained from the GWAS Catalog. A combined two-sample Mendelian randomization (MR), summary data-based Mendelian randomization (SMR), and mediation analyses were performed to investigate the causal link between Glutaryl-CoA dehydrogenase (GCDH) and RM, with a specific focus on glutarylcarnitine metabolism.</p><p><strong>Results: </strong>MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, P = 0.0045). Mediation analysis revealed that elevated GCDH expression significantly reduced glutarylcarnitine (C5-DC) levels, which in turn was inversely associated with RM risk. A three-step MR-based mediation confirmed a significant mediating effect of glutarylcarnitine (β₁₂ = 0.0680, P = 0.002), with 30.25% of the total effect attributable to it. The robustness of these findings was further demonstrated by sensitivity analyses and SMR results.</p><p><strong>Conclusion: </strong>This study represents the first evidence that GCDH might exert an indirect pro-RM effect via the downregulation of glutarylcarnitine, thus providing new insights into tumor metabolic pathways and positioning glutarylcarnitine as a potentially diagnostic biomarker and therapeutic target for RM.</p>\",\"PeriodicalId\":11148,\"journal\":{\"name\":\"Discover. 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引用次数: 0
摘要
背景：Crotonylation是最近发现的赖氨酸酰化，在翻译后修饰[1]中起关键作用。它通过调节代谢重编程[2]、DNA修复、免疫逃避[3]和致癌信号通路（包括PKA-FAK-AKT和雄激素受体信号通路[4]）参与肿瘤发生。巴豆酰化在肾恶性肿瘤（RM）中的具体作用尚不清楚，特别是与基因表达和代谢途径的相互作用。方法：本研究整合了FinnGen数据库中RM的全基因组关联研究（GWAS）汇总统计数据、eQTLGen联盟中巴豆酰化相关基因表达数据以及GWAS目录中代谢物GWAS数据。通过双样本孟德尔随机化（MR）、基于汇总数据的孟德尔随机化（SMR）和中介分析，研究戊二酰辅酶A脱氢酶（GCDH）与RM之间的因果关系，特别关注戊二酰肉碱代谢。结果：MR分析显示有显著相关性；GCDH表达增加可能增加RM的风险（OR = 1.25, P = 0.0045）。中介分析显示，GCDH表达升高可显著降低戊二酰肉碱（C5-DC）水平，从而与RM风险呈负相关。三步磁共振介导证实戊二酰肉碱具有显著的中介作用（β₁₂= 0.0680,P = 0.002），占总效应的30.25%。敏感性分析和SMR结果进一步证明了这些发现的稳健性。结论：本研究首次证明GCDH可能通过下调戊二酰肉碱间接促进RM的作用，从而为肿瘤代谢途径提供了新的认识，并将戊二酰肉碱定位为RM的潜在诊断生物标志物和治疗靶点。
Background: Crotonylation, a recently identified lysine acylation, plays a critical role in post-translational modifications [1]. It has been implicated in tumorigenesis by modulating metabolic reprogramming [2], DNA repair, immune evasion [3], and oncogenic signaling pathways, including PKA-FAK-AKT and androgen receptor signaling [4]. The specific role of crotonylation in renal malignancy (RM) remains poorly understood, especially in interaction with gene expression and metabolic pathway interactions.
Methods: This study integrates genome-wide association study (GWAS) summary statistics for RM from the FinnGen database, data on crotonylation-associated gene expression obtained from the eQTLGen consortium, and metabolite GWAS data obtained from the GWAS Catalog. A combined two-sample Mendelian randomization (MR), summary data-based Mendelian randomization (SMR), and mediation analyses were performed to investigate the causal link between Glutaryl-CoA dehydrogenase (GCDH) and RM, with a specific focus on glutarylcarnitine metabolism.
Results: MR analysis demonstrated a significant association; increased expression of GCDH is likely to increase the risk of RM (OR = 1.25, P = 0.0045). Mediation analysis revealed that elevated GCDH expression significantly reduced glutarylcarnitine (C5-DC) levels, which in turn was inversely associated with RM risk. A three-step MR-based mediation confirmed a significant mediating effect of glutarylcarnitine (β₁₂ = 0.0680, P = 0.002), with 30.25% of the total effect attributable to it. The robustness of these findings was further demonstrated by sensitivity analyses and SMR results.
Conclusion: This study represents the first evidence that GCDH might exert an indirect pro-RM effect via the downregulation of glutarylcarnitine, thus providing new insights into tumor metabolic pathways and positioning glutarylcarnitine as a potentially diagnostic biomarker and therapeutic target for RM.
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