Genome-wide DNA methylation in HIV infected drug users

HIV 感染吸毒者的全基因组 DNA 甲基化

• 批准号: 9015756
• 负责人: KE XU
• 金额: $ 12.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015756
• 关键词: 6q21; African American; Aging; Alcohol consumption; Alcohol or Other Drugs use; Antiviral Agents; Bioinformatics; Blood Cells; Blood specimen; CD4 Lymphocyte Count; Chromosomes; Cohort Studies; DNA; DNA Methylation; DNA Sequence; Data; Development; Drug abuse; Drug user; Environmental Risk Factor; Epigenetic Process; Evaluation; Funding; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; Health; Human; Immune; Immune response; Individual; Inflammatory; Injection of therapeutic agent; Lead; Light; Linear Models; Major Histocompatibility Complex; Methylation; Molecular; Nature; Nicotine; Nucleic Acid Regulatory Sequences; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pilot Projects; Population; Positioning Attribute; Predisposition; Process; Quantitative Trait Loci; Research Personnel; Risk; Role; Route; Sample Size; Sampling; Sexual Transmission; Single Nucleotide Polymorphism; Site; Technology; Testing; TimeLine; Veterans; Viral Load result; base; bead chip; cohort; demographics; epigenome; functional genomics; genetic variant; genome wide methylation; genome-wide; immune function; intravenous drug use; male; methylation pattern; methylome; novel; preclinical study; therapy development; transmission process

 DESCRIPTION (provided by applicant): Intravenous drug use (IDU) is common among HIV-infected individuals and has been associated with HIV exposure, transmission, and progression. Preclinical studies have demonstrated that IDU compromises immune function and alters the inflammatory process. However, little is known about the molecular mechanisms of interplay between IDU and HIV infection. DNA methylation modulates gene expression without changing DNA sequence and is regulated by environmental (e.g. IDU, nicotine/alcohol use, and antiviral exposure) and genetic factors. We hypothesize that IDU may change host genome vulnerability for HIV infection by modifying DNA methylation. Methylation changes resulting from IDU can be regulated by genetic variants called methylation quantitative trait loci (mQTL). In this project, w aim 1) to identify genome-wide methylation marks for HIV-positive IDU in blood samples from 768 HIV-positive African American (AA) males with and without IDU. We will profile 480,000 methylation sites using the Illlumina Human Methylation 450K Beadchip (450K array); 2) to identify cis-mQTL for HIV-positive IDU versus non-IDU. Taking advantage of available genotypes for 980,000 single nucleotide polymorphisms (SNPs), we will conduct cis-mQTL (SNP near to its target CpG site) analysis. To prove feasibility, we have conducted a pilot study with 384 samples from AA male HIV- positive subjects using the 450K array. We found that CD4 count was lower in IDUs than non- IDUs. Methylation on the HLA-DQB2 was inversely correlated with CD4 count. Methylation on HLA-DMA gene was significantly higher in IDU than non-IDU. Based on these encouraging preliminary results, we expect to identify global methylation marks for comorbid of HIV and IDU with an increase of the sample size to 768. The project would be the largest evaluation if DNA methylation changes among HIV-positive IDU in AAs. The findings could open a new avenue for development of treatments for HIV-positive IDU because of the reversible nature of DNA methylation. The results from this project shall lead a R01 application to further understand the interaction of drug abuse and HIV infection using the integrated functional genomic approach for a new investigator. Long-term objective: We aim to integrate genome and methylome information to better understand the interaction between drug abuse and HIV infection.

 描述（由申请人提供）：静脉注射药物使用（IDU）在HIV感染者中很常见，并与HIV暴露、传播和进展相关。临床前研究表明，IDU损害免疫功能并改变炎症过程。然而，对IDU和HIV感染之间相互作用的分子机制知之甚少。DNA甲基化在不改变DNA序列的情况下调节基因表达，并受环境（如IDU、尼古丁/酒精使用和抗病毒药物暴露）和遗传因素的调节。我们推测IDU可能通过改变DNA甲基化改变宿主基因组对HIV感染的易感性。IDU引起的甲基化变化可以通过称为甲基化数量性状基因座（mQTL）的遗传变异来调节。本研究的目的是：1）从768例有或无IDU的HIV阳性非裔美国人（AA）男性血液样本中鉴定HIV阳性IDU的全基因组甲基化标记。我们将使用Illumina Human Methylation 450 K Beadchip（450 K阵列）分析480，000个甲基化位点; 2）鉴定HIV阳性IDU与非IDU的顺式mQTL。利用980，000个单核苷酸多态性（SNP）的可用基因型，我们将进行cis-mQTL（靠近其目标CpG位点的SNP）分析。为了证明可行性，我们使用450 K阵列对来自AA男性HIV阳性受试者的384个样本进行了初步研究。我们发现静脉吸毒者的CD_4计数低于非静脉吸毒者。HLA-DQB 2甲基化与CD 4计数呈负相关。IDU组HLA-DMA基因甲基化水平显著高于非IDU组。基于这些令人鼓舞的初步结果，我们希望通过将样本量增加到768个来确定HIV和IDU共病的全球甲基化标记。如果DNA甲基化在AA中的HIV阳性IDU中发生变化，该项目将是最大的评估。由于DNA甲基化的可逆性，这些发现可能为开发艾滋病毒阳性注射吸毒者的治疗方法开辟一条新途径。该项目的结果将导致R 01应用，以进一步了解药物滥用和HIV感染的相互作用，使用整合的功能基因组方法为新的研究者。长期目标：我们的目标是整合基因组和甲基化组信息，以更好地了解药物滥用和艾滋病毒感染之间的相互作用。