Feature selection of DNA methylation biosignatures for neuropathy with comorbid drug abuse in the setting of HIV infection

远端感觉性多发性神经病(DSPN)仍然是HIV感染患者最常见的神经系统并发症 人口。鸦片类药物和可卡因经常被滥用来控制神经性疼痛。这些药物反过来又增加了 增加DSPN的风险，加重DSPN的严重程度。DSPN与物质使用障碍(SUD)的相互作用是 与艾滋病毒感染者的发病率和死亡率有关。尽管HIV-1gp120的神经毒性作用 而抗逆转录病毒药物通过调节致炎基因的失调而导致DSPN，几乎没有 了解DSPN和DSPN合并SUD的发病机制。推进我们的 对DSPN的理解是活着的人无法接触到神经组织，缺乏可靠的 在SUD和HIV感染的情况下，生物标志物为DSPN的诊断提供信息。我们的首要目标是 发现DSPN、SUD及其共病的DNA甲基化特征。我们关注的是白细胞 (WBC)，因为它们在协调和影响免疫反应方面的作用，以及因为它们高度 无障碍纸巾。我们假设DSPN是在HIV-1感染HIV的背景下出现的 在包括白细胞在内的许多细胞类型中，促炎基因的表达增强。我们还假设 DSPN的出现是由于WBC中促炎基因表达增强的结果。因此，DNA WBC中的甲基化与DSPN有关，DSPN受到SUD的影响，并有助于HIV的结局。 为了验证假设，我们将选择WBC中DSPN、SUD及其共病的甲基化特征。 表观基因组关联研究和基于集成的机器学习的结合 接近了。利用两个成熟的独立队列，我们将首先在 2,000例HIV感染者中DSPN和SUD的WBC分为DSPN+/SUD+、DSPN+/SUD-、DSPN-/SUD+、DSPN-/SUD- 感染的样本使用两阶段的EWAS，然后是Meta-Ewas。然后我们将选择甲基化特征 使用机器学习方法，并测试敏感性和特异性，以区分DSPN、SUD和它们的 合并症。我们将应用我们内部开发的生物信息包SmartFeatureSelection。这个 选定的特征将测试与免疫弹性(即CD4+/CD8+)和艾滋病毒结局(即脆弱， 死亡率)。最后，我们将探索已识别的甲基化位点在人类死后的生物学功能 脑组织和血液(N=80)的RNA-SEQ检测及其与白细胞和白细胞之间甲基化调控基因表达的相关性 神经细胞。我们希望发现一组具有生物学意义的甲基化特征，作为HIV的标志- 感染的DSPN和SUD可以预测复原力和预后。 这个应用程序采用了严格的设计和强大的计算方法，提出了第一个 基于表观基因组对DSPN、SUD及其相互作用的预测。所识别的特征可以用作 这一复杂疾病的生物标志物具有潜在的临床应用价值。这一结果将提高人们对 HIV感染的DSPN和SUD在血液和脑中的表观遗传机制。

Distal sensory polyneuropathy (DSPN) remains the most common neurological complication in HIV-infected population. Opiates and cocaine are often misused to manage neuropathic pain. These drugs, in turn, increase the risk of DSPN and exacerbate DSPN severity. The interplay of DSPN and substance use disorder (SUD) is associated with morbidity and mortality in HIV-infected individuals. Although neurotoxic effects of HIV-1 gp120 and antiretroviral medications contribute to DSPN through dysregulation of pro-inflammation genes, little is known about the mechanisms of DSPN and DSPN with comorbid SUD. A major barrier to advancing our understanding of DSPN is the inaccessibility of nerve tissues in living individuals and the absence of reliable biomarkers to inform the diagnosis of DSPN in the setting of SUD and HIV infection. Our overarching goal is to discover the DNA methylation signatures for DSPN, SUD, and their comorbidity. We focus on white blood cells (WBCs) because of their role in orchestrating and effecting immune responses and because they are highly accessible tissues. We hypothesize that DSPN emerges in the context of HIV infection as the result of HIV-1 enhanced expression of proinflammatory genes in many cell types, including WBCs. We also hypothesize that DSPN emerges as the result of SUD-enhanced expression of proinflammatory genes in WBCs. Thus, DNA methylation in WBCs is associated with DSPN that is influenced by SUD and contributes to HIV outcomes. To test the hypotheses, we will select methylation features in WBCs for DSPN, SUD, and their comorbidity using a combination of epigenome-wide association study (EWAS) and ensemble-based machine learning approaches. Leveraging two well-established independent cohorts, we will first identify methylation sites in WBCs for DSPN and SUD in four groups (DSPN+/SUD+, DSPN+/SUD-, DSPN-/SUD+, DSPN-/SUD-) in 2,000 HIV- infected samples using a 2-stage EWAS followed by a meta-EWAS. We will then select methylation features using machine learning methods and test the sensitivity and specificity to differentiate DSPN, SUD, and their comorbidity. We will apply our in-house developed bioinformatic package, smartFeatureSelection. The selected features will test associations with immune resilience (i.e. CD4+/CD8+) and HIV outcomes (i.e. frailty, mortality). Finally, we will explore the biological functions of the identified methylation sites in postmortem human brain and blood (N = 80) by RNA-seq and correlate methylation-regulated gene expression between WBCs and neural cells. We expect to discover a set of biologically meaningful methylation features as a marker for HIV- infected DSPN and SUD that can predict resilience and outcomes. Employing a rigorous design and a powerful computational approach, this application proposes the first epigenome-based prediction for DSPN, SUD, and their interaction. The identified features can serve as a biomarker for this complex condition and have potential clinical use. The results will enhance the knowledge of epigenetic mechanisms in blood and in brain for HIV-infected DSPN and SUD.