Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

基本信息

批准号：
10596624
负责人：
David W Haas
金额：
$ 81.67万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-08 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596624
关键词：
AIDS clinical trial group Acceleration Affect Anti-Retroviral Agents Antiviral Agents Biology Cells Chronic Clinical Clinical Trials Collaborations Complement Complex Genetic Trait Computerized Medical Record Data Data Analyses Data Set Databases Drug Interactions Drug Kinetics Drug toxicity Epidemiology Exogenous Factors FDA approved Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Polymorphism Genetic Transcription Genome Genomic approach Genotype Goals HIV HIV therapy HIV-1 Heritability Human Genetics Human Genome Immune Individual Infection Inflammation Injectable Intervention Intervention Trial Laboratories Messenger RNA Metabolism Methodology Organ Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacogenomics Phenotype Predisposition Randomized Recovery Research Research Personnel Risk Single Nucleotide Polymorphism Specimen System Tablets Technology Therapeutic Intervention Tissue-Specific Gene Expression Tissues Toxic effect Transcript Translating Treatment-related toxicity United States Variant Virus Replication Visualization Work absorption antiretroviral therapy clinical care clinical effect clinically relevant cohort endophenotype genetic association genetic variant genome wide association study genome-wide genomic data immune activation improved inter-individual variation interest non-genetic novel novel therapeutics phenome polygenic risk score prevent prospective response trait transcriptome treatment response whole genome

项目摘要

PROJECT SUMMARY Approximately 1.2 million individuals in the United States and 38 million worldwide are living with HIV. Priorities for HIV research include cure, mitigating associated inflammation and immune activation, novel therapeutics, and optimizing current management. In addition, there remains detrimental interindividual variability in HIV treatment responses regarding toxicities and immune recovery. Efforts to decipher relationships between the human genome and responses to therapeutic interventions in people living with HIV will help drive continued progress in the field, and involve complementary methodologies. The well-established value of the genome- wide association study (GWAS) is expanded by considering the polygenic risk score (PRS), which considers numerous polymorphisms that, in combination, affect risk for a phenotype, and by the integrated risk score (IRS), which combines PRS with non-genetic exposures. It is further expanded by the transcriptome-wide association study (TWAS), which relies on heritable gene expression in over 40 tissues throughout the body, inferred from genome-wide genotype data, and by the phenome-wide association study (PheWAS), which simultaneously interrogates genotype-phenotype associations across vast numbers of phenotypes. Complementing these variant-based and gene-based approaches are powerful wet-lab direct bulk and single- cell transcriptome analyses (TA) that decipher underlying biology by comparing patterns of gene expression between different experimental conditions or phenotypes. Building on progress to date, we will apply these complementary approaches to decipher genetic underpinnings of HIV-relevant clinical and endophenotypes, largely through analyses of available data and specimens from numerous different AIDS Clinical Trials Group trials and cohorts. We will consider interventions that target inflammation, the HIV reservoir, viral replication, and beyond. This work is facilitated by extensive groundwork laid by the proposing investigators to create and implement efficient, robust systems for variant-based, gene-based, and RNA expression-based genomic data generation and data analysis, as well as interpretation and visualization of results. Our ultimate goal is to improve the lives of people living with HIV through accelerated discovery based on state-of-the-art genomic approaches.

项目概要美国大约有 120 万人，全世界大约有 3800 万人感染艾滋病毒。优先事项 HIV 研究包括治愈、减轻相关炎症和免疫激活、新疗法、并优化现有管理。此外，艾滋病毒的个体间差异仍然存在。有关毒性和免疫恢复的治疗反应。努力破译两者之间的关系人类基因组和艾滋病毒感染者对治疗干预的反应将有助于推动持续该领域的进展，并涉及补充方法。基因组的公认价值广泛关联研究（GWAS）通过考虑多基因风险评分（PRS）进行了扩展，该评分考虑了许多多态性结合起来影响表型的风险，并通过综合风险评分 (IRS)，它将 PRS 与非基因暴露结合起来。它通过转录组范围进一步扩展关联研究 (TWAS)，依赖于全身 40 多个组织中的可遗传基因表达，根据全基因组基因型数据和全表型关联研究 (PheWAS) 推断，同时询问大量表型的基因型-表型关联。对这些基于变体和基于基因的方法的补充是强大的湿实验室直接批量和单一细胞转录组分析 (TA)，通过比较基因表达模式来解读潜在生物学不同的实验条件或表型之间。基于迄今为止的进展，我们将应用这些解读艾滋病毒相关临床和内表型的遗传基础的补充方法，主要通过对来自众多不同艾滋病临床试验组的可用数据和样本进行分析试验和队列。我们将考虑针对炎症、艾滋病毒储存库、病毒复制、以及更远的地方。提议的调查人员为创建和建立广泛的基础奠定了广泛的基础，从而促进了这项工作为基于变异、基于基因和基于 RNA 表达的基因组数据实施高效、稳健的系统生成和数据分析，以及结果的解释和可视化。我们的最终目标是通过基于最先进基因组的加速发现来改善艾滋病毒感染者的生活接近。

项目成果

期刊论文数量（45）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacogenetics of efavirenz discontinuation for reported central nervous system symptoms appears to differ by race.

DOI：
10.1097/fpc.0000000000000238
发表时间：
2016-10
期刊：
Pharmacogenetics and genomics
影响因子：
2.6
作者：
Leger P;Chirwa S;Turner M;Richardson DM;Baker P;Leonard M;Erdem H;Olson L;Haas DW
通讯作者：
Haas DW

Treatment Failure, Drug Resistance, and CD4 T-Cell Count Decline Among Postpartum Women on Antiretroviral Therapy in South Africa.

DOI：
10.1097/qai.0000000000000811
发表时间：
2016-01-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Hoffmann CJ;Cohn S;Mashabela F;Hoffmann JD;McIlleron H;Denti P;Haas DW;Dooley KE;Martinson NA;Chaisson RE
通讯作者：
Chaisson RE

Another Round of "Clue" to Uncover the Mystery of Complex Traits.

DOI：
10.3390/genes9020061
发表时间：
2018-01-25
期刊：
Genes
影响因子：
3.5
作者：
Verma SS;Ritchie MD
通讯作者：
Ritchie MD

Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.

DOI：
10.1097/qad.0b013e328360dbb4
发表时间：
2013-07-31
期刊：
AIDS (London, England)
影响因子：
0
作者：
McIlleron HM;Schomaker M;Ren Y;Sinxadi P;Nuttall JJ;Gous H;Moultrie H;Eley B;Merry C;Smith P;Haas DW;Maartens G
通讯作者：
Maartens G

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid.