Sullivan Shannon M, Cole Ben, Lane John, Meredith John J, Langer Erica, Hooten Anthony J, Roesler Michelle, McGraw Kathy L, Pankratz Nathan, Poynter Jenny N
Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Hum Mol Genet. 2023 Oct 4;32(20):2996-3005. doi: 10.1093/hmg/ddad126.
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. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. et al. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li et al. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. et al. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000 bp increase in LTL, 95% CI: 1.03, 6.52 using Taub et al. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. et al. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] 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.
长期以来，人们已经认识到维持端粒长度在癌症生物学中发挥作用，多项研究表明，这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反向因果关系的潜在偏差，我们使用多基因风险评分（PRS）和逆方差加权（IVW）孟德尔随机化（MR）分析来估计498例急性髓系白血病（AML）患者和2099例对照中基因预测的白细胞端粒长度（LTL）与AML风险之间的关系，以及610例骨髓增生异常综合征（MDS）患者和1759例对照中基因预测的LTL与MDS风险之间的关系。我们考虑了来自最近四项研究的遗传工具，这些工具解释了1.23%-4.57%的端粒变异性。我们使用多变量逻辑回归来估计优势比（OR，95%置信区间[CI]），作为个体单核苷酸多态性与髓系恶性肿瘤之间关联的度量。我们观察到，使用三种遗传工具，预测LTL较长的PRS与AML之间存在显著关联（使用Codd等人[Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I.等人（2013年）鉴定影响平均端粒长度的七个基因座及其与疾病的关联。《自然遗传学》，45，422-427 427e421-422。]的工具，LTL每增加约1200个碱基对[bp]时，OR = 4.03，95% CI：1.65，9.85；使用Li等人[Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C.等人（2020年）人类全基因组关联分析将核苷酸代谢与白细胞端粒长度联系起来。《美国人类遗传学杂志》，106，389-404。]的工具，LTL每增加一个标准差时，OR = 3.48，95% CI：1.7, 6.97；使用Taub等人[Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M.等人（2022年）TOPMed中109,122个不同祖先的全基因组序列的端粒长度遗传决定因素。《细胞基因组学》，2。]的工具，LTL每增加1000 bp时，OR = 2.59，95% CI：1.03，6.52）。MR分析进一步表明LTL与AML风险之间存在关联（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变异可能在AML的病因学中起重要作用，但在MDS中并非如此。
