长久以来，保持端粒长度在癌症生物学中的作用已经被广泛确认，并且一些研究表明，在髓系恶性肿瘤中可能尤为重要。为了克服观察性研究中混杂因素和逆向因果关系的潜在偏差，我们同时采用了多基因风险评分（PRS）和逆方差加权（IVW）门迪利安随机化（MR）分析，估计基因预测的白细胞端粒长度（LTL）与急性髓系白血病（AML）风险和骨髓增生异常综合征（MDS）风险之间的关系。我们使用了解释端粒变异性1.23-4.57%的四个最近的研究得到的遗传工具。我们使用多变量 logistic 回归估计单个单核苷酸多态性与髓系恶性肿瘤之间的关联度（OR, 95% CI）。我们观察到，使用三个遗传工具，预测LTL较长的PRS与AML之间存在显著关联（OR = 每1200个碱基对（bp）LTL增加4.03，95% CI: 1.65, 9.85，使用Codd et al. [2013]；OR = 每个标准差LTL增加3.48，95% CI: 1.74, 6.97，使用Li et al. [2020]；OR = 每1000 bp LTL增加2.59，95% CI: 1.03, 6.52，使用Taub et al. [2022]）。MR分析进一步表明，LTL与AML风险存在关联（PIVW ≤ 0.049），但与MDS风险无关（所有PIVW ≥ 0.076）。研究结果表明，与端粒功能和维持相关的基因的变异在AML的发病机制中可能具有重要作用，但对MDS的发病机制则不具备重要性。© The Author(s) 2023. Published by Oxford University Press. All rights reserved. 请联系 journals.permissions@oup.com 获取使用权限。

Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per~1200 base pair [bp] increase in LTL, 95% CI:1.65, 9.85 using Codd et al. [2013], OR = 3.48 per one-standard deviation increase in LTL, 95% CI:1.74, 6.97 using Li et al. [2020], and OR = 2.59 per 1000 bp increase in LTL, 95% CI:1.03, 6.52 using Taub et al. [2022] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.