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

HIV 感染背景下合并药物滥用的神经病 DNA 甲基化生物印记的特征选择

• 批准号: 10404953
• 负责人: Bradley E Aouizerat
• 金额: $ 56.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404953
• 关键词: Advanced Development; Aging; Anti-Retroviral Agents; Association Learning; Autopsy; Bioinformatics; Biological Markers; Biological Process; Blood; Brain; CD8B1 gene; Clinical; Cocaine; Cocaine use disorder; Cohort Studies; Complex; Complication; DNA Methylation; Diagnosis; Disease Outcome; Distal; Drug abuse; Epigenetic Process; Fingerprint; Functional disorder; Gene Expression; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Immune; Immune response; Impairment; Individual; Infection; Inflammation; Inflammatory; Knowledge; Leukocytes; Light; Link; Machine Learning; Methods; Methylation; Modeling; Molecular; Morbidity - disease rate; Nerve Tissue; Neurologic; Neurons; Neuropathy; Opioid; Outcome; Pattern; Performance; Pharmaceutical Preparations; Polyneuropathy; Population; Prevalence; Protocols documentation; Risk; Role; Sampling; Sensitivity and Specificity; Sensory; Severities; Signal Transduction; Site; Substance Use Disorder; Syndrome; Testing; Thalamic structure; Tissues; Veterans; Women' s Interagency HIV Study; base; biosignature; brain tissue; cell type; cohort; comorbidity; design; drug misuse; epigenome; epigenome-wide association studies; epigenomics; feature selection; frailty; immune function; machine learning method; model building; mortality; neurotoxic; novel; opioid use; painful neuropathy; predictive modeling; resilience; substance misuse; transcriptome sequencing

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.

远端感觉性多发性神经病（DSPN）仍然是HIV感染者最常见的神经系统并发症。 人口阿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， DSPN的风险并加重DSPN的严重程度。DSPN和物质使用障碍（SUD）的相互作用是 与HIV感染者的发病率和死亡率相关。虽然HIV-1 gp 120的神经毒性作用 抗逆转录病毒药物通过促炎症基因的失调导致DSPN， 了解DSPN和DSPN合并SUD的机制。一个主要的障碍，以推进我们的 对DSPN的理解是活体中神经组织的不可接近性和缺乏可靠的 在SUD和HIV感染的情况下，生物标志物可以为DSPN的诊断提供信息。我们的首要目标是 发现DSPN、SUD及其共患病的DNA甲基化特征。我们专注于白色血细胞 白细胞（WBC），因为它们在协调和影响免疫反应中的作用，并且因为它们是高度 可获取的组织。我们假设DSPN是在HIV感染的背景下出现的，是HIV-1的结果。 促炎基因在包括白细胞在内的多种细胞类型中的表达增强。我们还假设， DSPN的出现是SUD增强WBC中促炎基因表达的结果。因此，DNA WBC中的甲基化与受SUD影响的DSPN相关，并有助于HIV结果。 为了检验假设，我们将使用以下方法选择DSPN、SUD及其合并症的WBC甲基化特征： 表观全基因组关联研究（EWAS）和基于集成的机器学习的组合 接近。利用两个建立良好的独立队列，我们将首先鉴定甲基化位点， 2,000名HIV-1感染者中，四组（DSPN+/SUD+、DSPN+/SUD-、DSPN-/SUD+、DSPN-/SUD-）的DSPN和SUD WBC 使用2阶段EWAS随后使用元EWAS对感染的样品进行检测。然后，我们将选择甲基化特征 使用机器学习方法，并测试区分DSPN，SUD及其 科摩罗。我们将应用我们内部开发的生物信息学软件包，smartpharmacureSelection。的 选定的特征将测试与免疫弹性（即CD 4 +/CD 8+）和HIV结果（即虚弱， 死亡率）。最后，我们将探讨所鉴定的甲基化位点在死后人体中的生物学功能 脑和血液（N = 80）通过RNA-seq和相关的甲基化调节的基因表达之间的WBC和 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的标志物。 受感染的DSPN和SUD可以预测弹性和结果。 采用严格的设计和强大的计算方法，本申请提出了第一个 基于表观基因组的DSPN、SUD及其相互作用的预测。所识别的特征可以用作 这种复杂病症的生物标志物，并具有潜在的临床用途。研究结果将增进对以下问题的认识： HIV感染的DSPN和SUD的血液和大脑中的表观遗传机制。

项目成果

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016.

国家 PTSD 相关失眠适应性试验（NAP 研究）的设计，VA 合作研究计划 (CSP)

• DOI: 10.1016/j.cct.2021.106540
• 发表时间: 2021
• 期刊: Contemporary clinical trials
• 影响因子: 2.2
• 作者: Krystal,JohnH;Chow,Bruce;Vessicchio,Jennifer;Henrie,AdamM;Neylan,ThomasC;Krystal,AndrewD;Marx,BrianP;Xu,Ke;Jindal,RipuD;Davis,LoriL;Schnurr,PaulaP;Stein,MurrayB;Thase,MichaelE;Ventura,Beverly;Huang,GrantD;Shih,Mei
• 通讯作者: Shih,Mei