Traditional Chinese Medicine Department of Immunology, Women & Children Health Institute Futian Shenzhen, Shenzhen, China.
First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
Front Immunol. 2024 May 21;15:1394438. doi: 10.3389/fimmu.2024.1394438. eCollection 2024.
Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or biomarkers to prevent AS, addressing the need for innovative and safe treatments.
We analyzed extensive data from protein quantitative trait loci (pQTLs) with up to 1,949 instrumental variables (IVs) and selected the top single-nucleotide polymorphism (SNP) associated with AS risk. Utilizing a two-sample Mendelian randomization (MR) approach, we assessed the causal relationships between identified proteins and AS risk. Colocalization analysis, functional enrichment, and construction of protein-protein interaction networks further supported these findings. We utilized phenome-wide MR (phenMR) analysis for broader validation and repurposing of drugs targeting these proteins. The Drug-Gene Interaction database (DGIdb) was employed to corroborate drug associations with potential therapeutic targets. Additionally, molecular docking (MD) techniques were applied to evaluate the interaction between target protein and four potential AS drugs identified from the DGIdb.
Our analysis identified 1,654 plasma proteins linked to AS, with 868 up-regulated and 786 down-regulated. 18 proteins (AGER, AIF1, ATF6B, C4A, CFB, CLIC1, COL11A2, ERAP1, HLA-DQA2, HSPA1L, IL23R, LILRB3, MAPK14, MICA, MICB, MPIG6B, TNXB, and VARS1) that show promise as therapeutic targets for AS or biomarkers, especially MAPK14, supported by evidence of colocalization. PhenMR analysis linked these proteins to AS and other diseases, while DGIdb analysis identified potential drugs related to MAPK14. MD analysis indicated strong binding affinities between MAPK14 and four potential AS drugs, suggesting effective target-drug interactions.
This study underscores the utility of MR analysis in AS research for identifying biomarkers and therapeutic drug targets. The involvement of Th17 cell differentiation-related proteins in AS pathogenesis is particularly notable. Clinical validation and further investigation are essential for future applications.
强直性脊柱炎（AS）是一种具有重要遗传成分的复杂疾病。本研究探讨了循环蛋白作为预防 AS 的潜在遗传药物靶点或生物标志物，以满足对创新和安全治疗的需求。
我们分析了来自蛋白质数量性状基因座（pQTLs）的广泛数据，其中包含多达 1949 个工具变量（IVs），并选择了与 AS 风险相关的顶级单核苷酸多态性（SNP）。利用两样本孟德尔随机化（MR）方法，我们评估了鉴定出的蛋白质与 AS 风险之间的因果关系。共定位分析、功能富集以及蛋白质-蛋白质相互作用网络的构建进一步支持了这些发现。我们利用全表型孟德尔随机化（phenMR）分析对这些蛋白质的药物靶点进行更广泛的验证和再利用。药物-基因相互作用数据库（DGIdb）用于证实与潜在治疗靶点相关的药物关联。此外，还应用分子对接（MD）技术评估了从 DGIdb 中确定的四种潜在 AS 药物与靶蛋白之间的相互作用。
我们的分析确定了 1654 种与 AS 相关的血浆蛋白，其中 868 种上调，786 种下调。有 18 种蛋白（AGER、AIF1、ATF6B、C4A、CFB、CLIC1、COL11A2、ERAP1、HLA-DQA2、HSPA1L、IL23R、LILRB3、MAPK14、MICA、MICB、MPIG6B、TNXB 和 VARS1）具有作为 AS 治疗靶点或生物标志物的潜力，特别是 MAPK14，这一结果得到了共定位证据的支持。phenMR 分析将这些蛋白与 AS 和其他疾病联系起来，而 DGIdb 分析则确定了与 MAPK14 相关的潜在药物。MD 分析表明 MAPK14 与四种潜在 AS 药物之间具有很强的结合亲和力，表明有效的靶-药物相互作用。
本研究强调了 MR 分析在 AS 研究中识别生物标志物和治疗药物靶点的效用。Th17 细胞分化相关蛋白在 AS 发病机制中的作用尤其值得关注。临床验证和进一步研究对于未来的应用至关重要。
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