Plasma microRNA expression in adolescents and young adults with endometriosis: the importance of hormone use

Paula Brady, Abdelrahman Yousif, Naoko Sasamoto, A. Vitonis, Wojciech Fendler, K. Stawiski, M. Hornstein, Kathryn L. Terry, Kevin M. Elias, Stacey Missmer, A. Shafrir
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Abstract

Introduction Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2−ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67–0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.
患有子宫内膜异位症的青少年的血浆 microRNA 表达:使用激素的重要性
导言:先前的研究已经调查了微RNA(miRNA)表达谱对子宫内膜异位症的诊断潜力。然而,之前的绝大多数研究只包括成年女性。因此,我们试图调查患有子宫内膜异位症的青少年和年轻成人中 miRNA 的不同表达情况。方法 妇女健康研究:从青春期到成年期(A2A)是一项正在进行的符合 WERF EPHect 标准的纵向队列研究。我们的分析包括 64 名经手术确诊的子宫内膜异位症患者(96% 为 rASRM I/II 期)和 118 名从未确诊过子宫内膜异位症的女性,她们的年龄(中位数 = 21 岁)与抽血时使用激素的频率相匹配。MicroRNA 测量分为发现阶段(10 个病例和 10 个对照)和内部复制阶段(54 个病例和 108 个对照)。在发现阶段,利用 PCR 和严格的内部对照措施检测 754 种血浆 miRNA 的水平,并利用 2-ΔΔCt 方法计算病例与对照组之间 miRNA 的相对表达量。内部复制阶段以 2:1 的比例分为训练集和测试集,并利用 FirePlex miRNA 分析法对神经网络分析中的 63 个 miRNA 进行评估。利用验证阶段的测试集计算训练集最佳拟合模型的曲线下面积(AUC),包括将激素的使用作为协变量。结果 在发现阶段,49 个 miRNA 在子宫内膜异位症病例和对照组之间有差异表达。抽血时使用激素的情况不同,这 49 个 miRNA 的关联也不同。对内部复制阶段测试集的神经网络分析确定了一个由 5 个 miRNAs(miR-542-3p、let-7b-3p、miR-548i、miR-769-5p、miR-30c-1-3p)组成的最终模型,其 AUC = 0.77(95% CI:0.67-0.87,p < 0.001)。与训练集相比,测试数据集的灵敏度提高了(83.3% 对 72.2%),而特异性降低了(58.3% 对 72.2%)。结论 研究结果表明,在患有子宫内膜异位症的青少年中,miR-542-3p、let-7b-3p、miR-548i、miR-769-5p、miR-30c-1-3p 可能存在失调。使用激素是导致 miRNA 失调的一个重要因素,在进行 miRNA 诊断研究时应严格考虑这一点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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