动态CD4+ T细胞遗传学识别变应性鼻炎的候选治疗靶点：孟德尔随机化与探索性单细胞情境化

文献信息

中文摘要

背景： 变应性鼻炎常见且临床异质性明显，但受遗传调控的免疫状态表达影响易感性的基因仍未完全明确。方法：我们将动态CD4+ T细胞eQTL数据（46种活化状态谱）与变应性鼻炎GWAS汇总统计量整合，应用全转录组孟德尔随机化（MR）、共定位、SMR/HEIDI、代谢物筛选、配对单细胞RNA-seq和TCR分析以及计算后续分析。共定位支持预先设定为条件比值PP.H4/(PP.H3 + PP.H4) > 0.7；HEIDI为p > 0.05。结果：排除MHC区域后，共检验50,654个基因-谱对，识别出129个MR显著基因。共定位支持418对（111个基因）；70个基因同时通过SMR和HEIDI；跨数据库比较得到9个基因的重叠集。在GSE200107中，基线良好应答者与不良应答者之间的差异大于治疗诱导的转录变化；患者水平再分析未发现任何对在多重检验校正后存活（n = 4 vs. 3）；这些发现具有假设生成性。配对TCR分析提示良好应答者中克隆型更新更多（描述性）。结构引导筛选优先选择了SLC25A46和TLR1的未验证结合剂候选物（TLR1 TIR对接 -5.86 kcal/mol；MD RMSD 0.20 nm）。结论：一项探索性代谢物筛选产生了名义显著的间接效应信号，但候选代谢物未与疾病位点共定位。该框架为变应性鼻炎优先确定了候选治疗靶点。

英文摘要

Background: Allergic rhinitis is common and clinically heterogeneous, but the genes whose genetically regulated immune-state expression influences susceptibility remain incompletely resolved. Methods: We integrated dynamic CD4+ T cell eQTL data (46 activation-state profiles) with allergic rhinitis GWAS summary statistics, applying transcriptome-wide Mendelian randomization (MR), colocalization, SMR/HEIDI, metabolite screening, paired single-cell RNA-seq and TCR analysis, and computational follow-up. Colocalization support was prespecified as conditional ratio PP.H4/(PP.H3 + PP.H4) > 0.7; HEIDI at p > 0.05. Results: After MHC-region exclusion, 50,654 gene-profile pairs were tested and 129 MR-significant genes were identified. Colocalization supported 418 pairs (111 genes); 70 genes passed both SMR and HEIDI; and cross-database comparison yielded a nine-gene overlap set. In GSE200107, baseline good-versus-poor responder differences were larger than treatment-induced transcriptional change; patient-level reanalysis found no pair surviving multiple-testing correction (n = 4 vs. 3); these findings are hypothesis-generating. Paired TCR analysis suggested greater clonotype renewal in good responders (descriptive). Structure-guided screening prioritized unvalidated binder candidates for SLC25A46 and TLR1 (TLR1 TIR docking -5.86 kcal/mol; MD RMSD 0.20 nm). Conclusions: An exploratory metabolite screen yielded nominally significant indirect-effect signals, but the candidate metabolite did not colocalize with the disease locus. This framework prioritizes candidate therapeutic targets for allergic rhinitis.