白血病的临床治疗靶点仍有待确定，白血病与端粒长度之间的因果关系尚不清楚。这项工作采用了来自 eQTLGen 联盟的 2,200 个可药物基因的顺式表达数量性状基因座 (eQTL) 和全基因组关联研究 (GWAS) 汇总数据来自英国生物银行、荷兰队列的七种血细胞类型的端粒长度作为暴露。 FinnGen 和 Lee 实验室的淋巴性白血病 (LL) 和髓性白血病 (ML) 的 GWAS 数据分别用作发现和复制队列的结果。稳健的孟德尔随机化 (MR) 结果是根据七个 MR 模型和一系列敏感性分析得出的。进一步实施基于汇总数据的 MR (SMR) 分析和全转录组关联研究 (TWAS)，以验证已识别的可药物基因与白血病之间的关联。采用单细胞类型表达分析来鉴定白血病偶然基因在人骨髓和外周血免疫细胞上的特异性表达。进行多变量MR分析、连锁不平衡评分回归（LDSC）和贝叶斯共定位分析，进一步验证端粒长度与白血病之间的关系。中介分析用于评估已确定的可药物基因通过端粒长度影响白血病的作用。全表型 MR (Phe-MR) 分析，用于评估白血病致病基因和端粒长度对 1,403 种疾病表型的影响。结合两个队列的 MR 估计荟萃分析结果、SMR 和 TWAS 分析，我们确定了 5 种 LL因果基因（TYMP、DSTYK、PPIF、GDF15、FAM20A）和三个 ML 因果基因（LY75、ADA、ABCA2）作为白血病有希望的药物靶点。单变量 MR 分析显示，基因预测的白细胞端粒长度较长会增加 LL 的风险（比值比 [OR] = 2.33，95% 置信区间 [95% CI] 1.70-3.18；P = 1.33E-07），并且不存在异质性和水平多效性。两个队列的荟萃分析证据强化了这一发现（OR = 1.88，95% CI 1.06-3.05；P = 0.01）。多变量 MR 分析显示白细胞端粒长度与 LL 之间的因果关系，不受其他六种血细胞端粒长度的干扰（OR = 2.72，95% CI 1.88-3.93；P = 1.23E-07）。 LDSC 的证据支持白细胞端粒长度与 LL 之间存在正向遗传相关性（rg = 0.309，P = 0.0001）。共定位分析表明，LL 上白细胞端粒长度的因果关系是由 TERT 区域的遗传变异 rs770526 驱动的。通过两步 MR 的中介分析表明，TYMP 对 LL 的因果效应部分是由白细胞端粒长度介导的，介导比例为 12%。我们的研究确定了几个与白血病风险相关的可药物基因，并为病因学提供了新的见解以及白血病的药物开发。我们还发现，基因预测的白细胞端粒长度较长会增加 LL 风险及其潜在作用机制。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear.This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %.Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.