NDLI: Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms

Content Provider	Springer Nature : BioMed Central
Author	Wang, Qiming Chen, Shaopeng Wang, Gang Zhang, Tielong Gao, Yulong
Abstract	Backgrounds A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. Methods Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the “TwoSampleMR” R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. Results Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001–1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P < 0.05). Moreover, the TCGA-KIRC, the ICGC-RC, and the GSE159115 datasets verified that the AFF3 gene was more highly expressed in RC tumors than normal control via scRNA-sequencing and bulk RNA-sequencing (P < 0.05). Gene set enrichment analysis (GSEA) analysis identified six potential biological pathways of AFF3 involved in RC. As for the potential mechanism of AFF3 in RC, we concluded in this article that AFF3 eQTL could negatively modulate the levels of the X-11,315 metabolite (IVW method; OR = 0.9127; 95% CI = 0.8530–0.9765; P = 0.0081; heterogeneity = 0.4150; pleiotropy = 0.8852), exhibiting preventive effects against RC risks (IVW method; OR = 0.9987; 95% CI = 0.9975–0.9999; P = 0.0380; heterogeneity = 0.5362; pleiotropy = 0.9808). Conclusions We concluded that AFF3 could serve as a novel eQTL-mediated susceptibility gene in RC and reveal its potential mechanism of elevating RC risks via negatively regulating the X-11,315 metabolite levels.
Related Links	https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-024-12513-1.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	14712407
DOI	10.1186/s12885-024-12513-1
Journal	BMC Cancer
Issue Number	1
Volume Number	24
Language	English
Publisher	BioMed Central
Publisher Date	2024-06-17
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Health Promotion and Disease Prevention Biomedicine Medicine Public Health Mendelian randomization eQTL SMR AFF3 Renal cancer Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology Genetics
Journal Impact Factor	3.4/2023
5-Year Journal Impact Factor	3.8/2023

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