Abstract: Background Long-term survivors of childhood acute lymphoblastic leukemia (ALL) have a markedly increased incidence of lipid metabolic disorders and a significantly elevated risk of cardiovascular disease. However, the causal relationship and shared genetic mechanisms between the two remain to be systematically clarified in East Asian populations. Objective To investigate the causal association and shared genetic basis between childhood ALL and lipid metabolic disorders in China, and to identify pleiotropic loci, functional genes, and potential therapeutic targets. Methods This study was based on summary statistics from a Chinese childhood ALL genome-wide association study, collected between January 2007 and September 2013 with authorized access from published literature (including 269 patients and 1 039 cancerfree controls). Bidirectional Mendelian randomization phenome-wide association studies (MR-PheWAS) were performed across 1 035 East Asian phenotypes, with validation in a European cohort comprising 197 ALL patients and 314 192 controls. Linkage disequilibrium score regression and integrated analysis of pleiotropy and annotation were used to evaluate genetic correlation and overlap. Pleiotropic loci were identified using the pleiotropic analysis under composite null hypothesis (PLACO) approach and functionally annotated using the Functional Mapping and Annotation (FUMA) platform. Summary-data-based Mendelian randomization (SMR) was used to screen shared functional genes, followed by pathway enrichment analysis and drug-gene interaction analysis to explore potential therapeutic targets. Results Forward MR analysis showed that higher BMI, eosinophil count, platelet count, and C-reactive protein levels were causally associated with an increased risk of childhood ALL. Reverse MR analysis indicated that ALL led to reduced levels of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A, blood glucose, and sex hormone-binding globulin, and increased levels of triglycerides (TG), low-density lipoprotein cholesterol, and liver enzyme levels. Validation in the European cohort further supported the causal association between ALL and TG, although the effect size (OR=0.99) was close to 1, suggesting limited clinical significance. Genetic analyses revealed significant genetic overlap between ALL and TG (P=1.95×10- 26) and between ALL and HDL-C (P=0.018). PLACO identified 158 pleiotropic single nucleotide polymorphisms (SNPs), which converged into 28 independent loci, including high-confidence variants such as LRRC16A [rs67245361, combined annotation dependent depletion (CADD) score=16.67] and HYKK (rs11852372). SMR analysis ultimately identified 57 shared functional genes (e.g., IFIT2, NPEPPS, and WDR81), which were mainly enriched in immune- and metabolism-related pathways. Drug gene interaction analysis identified 49 candidate compounds targeting 13 shared genes, including elotuzumab targeting GPR27 and ANTAQ targeting NPEPPS. Conclusion This study reveals a robust causal association and shared genetic basis between childhood ALL and lipid metabolic disorders, providing new genetic evidence and translational directions for long-term metabolic health management and targeted therapeutic strategies in ALL survivors.

Key words: Acute lymphoblastic leukemia, Lipid metabolism, Child, Mendelian randomization analysis, Genetic pleiotropy, Drug-gene interaction

摘要： 背景 儿童急性淋巴细胞白血病（ALL）长期幸存者的脂代谢紊乱发生率显著增高，心血管疾病风险明显上升，但两者间的因果关系及共享遗传机制在东亚人群中尚待系统阐明。目的 探讨中国儿童ALL与脂代谢紊乱之间的因果关联及共享遗传基础，识别多效性基因座、功能基因及潜在治疗靶点。方法 本研究基于已发表文献授权获取的于2007年1月—2013年9月收集的中国儿童ALL全基因组关联研究汇总统计数据（纳入269例患儿及1 039名无癌对照），对1 035个东亚人群表型开展双向孟德尔随机化全表型组关联研究（MR-PheWAS），并在欧洲队列（197例ALL患者及314 192名对照）中进行验证。采用连锁不平衡分数回归与整合多效性及注释的遗传分析，评估遗传相关性与重叠程度。通过复合零假设下的多效性分析（PLACO）识别多效性基因座，并借助遗传关联的功能映射与注释（FUMA）平台进行功能注释。基于汇总数据的孟德尔随机化（SMR）筛选共享功能基因，进一步通过通路富集分析与药物-基因互作分析探索潜在治疗靶点。结果 正向MR分析显示，较高BMI、嗜酸性粒细胞计数、血小板计数及C反应蛋白水平与儿童ALL发病风险增加存在因果关联。反向MR分析提示，ALL会导致高密度脂蛋白胆固醇（HDL-C）、载脂蛋白 A、血糖及性激素结合球蛋白水平降低，并导致甘油三酯（TG）、低密度脂蛋白胆固醇和肝酶水平升高。在欧洲人群队列中的验证进一步支持了ALL与TG之间的因果关联，但效应值（OR=0.99）接近1，提示其临床意义有限。遗传学分析揭示了ALL与TG（P=1.95×10-26）及ALL与HDL-C（P=0.018）之间存在显著的遗传重叠。PLACO分析鉴定出158个多效性单核苷酸多态性（SNP），这些位点汇聚于28个独立基因座，包含LRRC16A［rs67245361，组合注释依赖型损耗（CADD）评分=16.67］与HYKK（rs11852372）等高置信度变异位点。SMR分析最终确定57个共享功能基因（如IFIT2、NPEPPS、WDR81），主要富集于免疫和代谢相关通路。药物-基因互作分析筛选出针对13个共享基因的49种候选化合物，包括靶向GPR27的埃罗妥珠单抗及靶向NPEPPS的ANTAQ。结论 本研究揭示了儿童ALL与脂代谢紊乱之间存在稳健的因果关联及共享遗传基础，为 ALL 幸存者的长期代谢健康管理与靶向治疗策略提供了新的遗传学依据与转化方向。

关键词: 急性淋巴细胞白血病, 脂代谢, 儿童：孟德尔随机化分析, 基因多效性, 药物 - 基因相互作用