PDF(Pubmed)
Abstract：
UNASSIGNED: Emerging research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may play a pivotal role in the treatment of primary glomerular diseases. This study was aimed to investigate potential pharmacological targets connecting SGLT2 inhibitors with IgA nephropathy (IgAN) and membranous nephropathy (MN).
UNASSIGNED: A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization analysis was used to identify potential connections between target genes and IgAN and MN. Then, Comparative Toxicogenomics Database (CTD) was employed to predict diseases associated with these target genes and SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin). Subsequently, phenotypic scan analyses were applied to explore the causal relationships between the predicted diseases and target genes. Finally, we analyzed the immune signaling pathways involving pharmacological target genes using the Kyoto encyclopedia of genes and genomes (KEGG).
UNASSIGNED: The results of MR analysis revealed that eight drug targets were causally linked to the occurrence of IgAN, while 14 drug targets were linked to MN. In the case of IgAN, LCN2 and AGER emerged as co-localized genes related to the pharmacological agent of dapagliflozin and the occurrence of IgAN. LCN2 was identified as a risk factor, while AGER was exhibited a protective role. KEGG analysis revealed that LCN2 is involved in the interleukin (IL)-17 immune signaling pathway, while AGER is associated with the neutrophil extracellular traps (NETs) signaling immune pathway. No positive co-localization results of the target genes were observed between two other SGLT2 inhibitors (canagliflozin and empagliflozin) and the occurrence of IgAN, nor between the three SGLT2 inhibitors and the occurrence of MN.
UNASSIGNED: Our study provided evidence supporting a causal relationship between specific SGLT2 inhibitors and IgAN. Furthermore, we found that dapagliflozin may act on IgAN through the genes LCN2 and AGER.
UNASSIGNED: A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization analysis was used to identify potential connections between target genes and IgAN and MN. Then, Comparative Toxicogenomics Database (CTD) was employed to predict diseases associated with these target genes and SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin). Subsequently, phenotypic scan analyses were applied to explore the causal relationships between the predicted diseases and target genes. Finally, we analyzed the immune signaling pathways involving pharmacological target genes using the Kyoto encyclopedia of genes and genomes (KEGG).
UNASSIGNED: The results of MR analysis revealed that eight drug targets were causally linked to the occurrence of IgAN, while 14 drug targets were linked to MN. In the case of IgAN, LCN2 and AGER emerged as co-localized genes related to the pharmacological agent of dapagliflozin and the occurrence of IgAN. LCN2 was identified as a risk factor, while AGER was exhibited a protective role. KEGG analysis revealed that LCN2 is involved in the interleukin (IL)-17 immune signaling pathway, while AGER is associated with the neutrophil extracellular traps (NETs) signaling immune pathway. No positive co-localization results of the target genes were observed between two other SGLT2 inhibitors (canagliflozin and empagliflozin) and the occurrence of IgAN, nor between the three SGLT2 inhibitors and the occurrence of MN.
UNASSIGNED: Our study provided evidence supporting a causal relationship between specific SGLT2 inhibitors and IgAN. Furthermore, we found that dapagliflozin may act on IgAN through the genes LCN2 and AGER.
摘要：
■新兴研究表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可能在原发性肾小球疾病的治疗中起关键作用。本研究旨在探讨SGLT2抑制剂与IgA肾病（IgAN）和膜性肾病（MN）的潜在药理靶点。
■使用公开的全基因组关联研究（GWAS）数据集进行单变量孟德尔随机化（MR）分析。共定位分析用于鉴定靶基因与IgAN和MN之间的潜在连接。然后，比较毒性基因组学数据库（CTD）用于预测与这些靶基因和SGLT2抑制剂（canagliflozin，dapagliflozin,和empagliflozin）。随后，表型扫描分析用于探索预测的疾病和靶基因之间的因果关系。最后,我们使用京都基因和基因组百科全书(KEGG)分析了涉及药理靶基因的免疫信号通路.
■MR分析结果显示，八个药物靶点与IgAN的发生有因果关系，而14个药物靶标与MN相关。在Igan的情况下,LCN2和AGER作为与达格列净和IgAN的发生有关的共同定位基因出现。LCN2被确定为危险因素，而AGER则表现出保护作用。KEGG分析显示,LCN2参与白细胞介素(IL)-17免疫信号通路,而AGER与中性粒细胞胞外陷阱（NETs）信号免疫途径有关。在另外两种SGLT2抑制剂（canagliflozin和empagliflozin）和IgAN的发生之间未观察到靶基因的阳性共定位结果，三种SGLT2抑制剂与MN的发生之间也没有关系。
■我们的研究提供了支持特定SGLT2抑制剂与IgAN之间因果关系的证据。此外，我们发现达格列净可能通过基因LCN2和AGER作用于IgAN。
■使用公开的全基因组关联研究（GWAS）数据集进行单变量孟德尔随机化（MR）分析。共定位分析用于鉴定靶基因与IgAN和MN之间的潜在连接。然后，比较毒性基因组学数据库（CTD）用于预测与这些靶基因和SGLT2抑制剂（canagliflozin，dapagliflozin,和empagliflozin）。随后，表型扫描分析用于探索预测的疾病和靶基因之间的因果关系。最后,我们使用京都基因和基因组百科全书(KEGG)分析了涉及药理靶基因的免疫信号通路.
■MR分析结果显示，八个药物靶点与IgAN的发生有因果关系，而14个药物靶标与MN相关。在Igan的情况下,LCN2和AGER作为与达格列净和IgAN的发生有关的共同定位基因出现。LCN2被确定为危险因素，而AGER则表现出保护作用。KEGG分析显示,LCN2参与白细胞介素(IL)-17免疫信号通路,而AGER与中性粒细胞胞外陷阱（NETs）信号免疫途径有关。在另外两种SGLT2抑制剂（canagliflozin和empagliflozin）和IgAN的发生之间未观察到靶基因的阳性共定位结果，三种SGLT2抑制剂与MN的发生之间也没有关系。
■我们的研究提供了支持特定SGLT2抑制剂与IgAN之间因果关系的证据。此外，我们发现达格列净可能通过基因LCN2和AGER作用于IgAN。
