背景:对锂(Li)的反应在双相情感障碍(BD)中是高度可变的。尽管经过几十年的研究,尚未一致确定对Li预防反应的临床预测因子。最近,我们开发了表观遗传甲基化特异性高分辨率熔解(MS-HRM)测定法,该测定法能够区分BD1型(BD-I)个体中的良好应答者(GR)与非应答者(NR)和Li。这项研究检查了临床和表观遗传标记的组合是否可以将NR与其他类型的Li反应者区分开。
方法:我们记录了64名BD-I患者的临床变量,这些变量可能与Li反应相关。对从外周血分离的DNA进行MS-HRM测定。我们使用反向逐步逻辑回归分析,然后进行受试者工作特征(ROC)曲线分析,以估计临床变量的性能,单独与表观遗传生物标志物结合,确定GR和部分响应者(PaR)与NR。
结果:开始时的极性,BD发病时的精神病症状和家族史根据Li反应正确分类了70%的个体(PaRGR=86%;NR=35%)。当与表观遗传生物标志物结合时,这三个临床变量加上酒精滥用(和一个DMR:差异甲基化区域)正确分类了86%的个体,提高PaR+GR(93%)和NR(70%)的预测。ROC分析显示曲线下面积从0.75(仅临床变量)改善至0.87(临床和表观遗传标记的组合)。
结论:联合临床预测因子和Li反应的DNA甲基化标记在临床实践中可能比单独依靠临床特征具有更大的实用性。
BACKGROUND: Response to lithium (Li) is highly variable in bipolar disorders (BD). Despite decades of research, no clinical predictor(s) of response to Li prophylaxis have been consistently identified. Recently, we developed epigenetic Methylation Specific High-Resolution Melting (MS-HRM) assays able to discriminate good responders (GR) from non-responders (NR) to Li in individuals with BD type 1 (BD-I). This
study examined whether a combination of clinical and epigenetic markers can distinguish NR from other types of Li responders.
METHODS: We recorded clinical variables that are potentially associated with Li response in 64 individuals with BD-I. MS-HRM assays were performed on DNA isolated from peripheral blood. We used backward stepwise logistic regression analyses, followed by receiver operating characteristic (ROC) curve analysis to estimate the performance of the clinical variables, alone then in combination with the epigenetic biomarkers, to identify GR and partial responders (PaR) vs NR.
RESULTS: Polarity at onset, psychotic symptoms at onset and family history of BD classified correctly 70% of individuals according to their Li response (PaR + GR = 86%; NR = 35%). When combined with the epigenetic biomarkers, these three clinical variables plus alcohol misuse (and one DMR: Differentially Methylated Region) correctly classified 86% of individuals, improving the prediction of PaR + GR (93%) and of NR (70%). The ROC analysis demonstrated an improvement in the area under the curve from 0.75 (clinical variables alone) to 0.87 (combination of clinical and epigenetic markers).
CONCLUSIONS: Combining clinical predictors and DNA methylation markers of Li response may have greater utility in clinical practice than relying on clinical characteristics alone.