Table_2_Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes.xlsx

BackgroundNumerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear.
MethodsMendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings.
ResultsAfter Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714–0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births.
ConclusionOur MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.

背景：既往多项观察性研究已揭示端粒长度（telomere length, TL）与不良妊娠结局（adverse pregnancy outcomes, APOs）之间存在相关性，但端粒长度对不良妊娠结局的具体影响仍未明确。
方法：本研究采用来自全基因组关联研究（genome-wide association studies, GWAS）的汇总数据开展孟德尔随机化（Mendelian randomization, MR）分析。以逆方差加权法（inverse variance weighted, IVW）作为主要分析方法，探究端粒长度与不良妊娠结局之间的因果关联。暴露数据来自针对英国生物银行（UK Biobank）表型进行IEU分析的全基因组关联研究数据集，共纳入472174名欧洲裔参与者。本研究从FinnGen联盟的全基因组关联研究数据集获取5种不良妊娠结局的汇总级数据。此外，本研究还校正了吸烟、饮酒、体重指数（body mass index, BMI）及活产胎数，开展多变量孟德尔随机化（multivariate MR, MVMR）分析。同时，我们进行了一系列严谨的敏感性分析，以进一步验证本研究孟德尔随机化结果的可靠性。
结果：经邦费罗尼校正与严格质量控制后，单变量孟德尔随机化（univariable MR, UVMR）分析显示，在逆方差加权模型中，较短的端粒长度与自然流产（spontaneous abortion, SA）风险升高显著相关（比值比[OR] = 0.815；95%置信区间[CI] = 0.714–0.930；P = 0.002），同时与早产（preterm birth, PTB）风险升高显著相关（OR = 0.758；95%CI = 0.632-0.908；P = 0.003）。在逆方差加权模型中，端粒长度与子痫前期（preeclampsia, PE）亦存在名义上的显著关联（OR = 0.799；95%CI = 0.651-0.979；P = 0.031）。但在5种统计模型中，未发现端粒长度与妊娠期糖尿病（gestational diabetes mellitus, GDM）（OR = 0.950；95%CI = 0.804-1.122；P = 0.543）或胎儿生长受限（fetal growth restriction, FGR）存在显著关联。此外，反向孟德尔随机化分析未发现不良妊娠结局对端粒长度存在显著因果效应。多变量孟德尔随机化分析显示，在校正吸烟、饮酒、体重指数及活产胎数后，端粒长度对自然流产的因果效应仍具有统计学意义。
结论：本孟德尔随机化研究提供了可靠证据，表明较短的端粒长度与自然流产风险升高相关，未来需进一步探究其潜在分子机制。单变量与多变量孟德尔随机化分析结果显示，端粒长度对早产、子痫前期、妊娠期糖尿病及胎儿生长受限风险的影响证据有限，提示既往观察性研究的结果可能存在混杂偏倚。