Pharmacogenomics of HIV Therapy

HIV治疗的药物基因组学

• 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
• 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

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.

项目摘要 美国约有120万人，全世界约有3800万人感染艾滋病毒。优先事项 艾滋病毒研究包括治愈，减轻相关的炎症和免疫激活，新的治疗方法， 优化当前管理。此外，在艾滋病毒感染者中， 关于毒性和免疫恢复的治疗反应。努力破译之间的关系 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继续 这一领域的进展，并涉及补充方法。基因组的公认价值- 通过考虑多基因风险评分（PRS）扩展了广泛关联研究（GWAS），其中考虑 许多多态性，在组合中，影响表型的风险，并通过综合风险评分 (IRS)该方法将PRS与非遗传暴露相结合。它通过全转录组进一步扩展 关联研究（TWAS），它依赖于全身40多个组织中的遗传基因表达， 根据全基因组基因型数据和全表型关联研究（PheWAS）推断， 同时询问大量表型之间的基因型-表型关联。 作为对这些基于变体和基于基因的方法的补充，强大的湿实验室直接批量和单克隆抗体 细胞转录组分析（TA），通过比较基因表达模式， 在不同的实验条件或表型之间。在迄今取得的进展的基础上，我们将 互补的方法来破译艾滋病毒相关的临床和内在表型的遗传基础， 主要是通过分析来自众多不同艾滋病临床试验组的可用数据和样本， 试验和队列。我们将考虑针对炎症、艾滋病毒储存库、病毒复制的干预措施， 以及更远的地方这项工作得到了提议的调查人员为创建和 为基于变体、基于基因和基于RNA表达的基因组数据实现高效、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 通过基于最先进的基因组学的加速发现，改善艾滋病毒感染者的生活 接近。

项目成果

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

Efavirenz停用的中枢神经系统症状的药物遗传学似乎因种族而有所不同。

• 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)
• 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

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid.

Tenofovir和Emtritebine渗透到脑脊液中的药物遗传学。

• DOI: 10.4102/sajhivmed.v22i1.1206
• 发表时间: 2021
• 期刊: Southern African journal of HIV medicine
• 影响因子: 1.7
• 作者: Decloedt EH;Sinxadi PZ;Wiesner L;Joska JA;Haas DW;Maartens G
• 通讯作者: Maartens G

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)
• 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