Pharmacogenetics of sulfamethoxazole in HIV/AIDS patients

HIV/AIDS 患者中磺胺甲恶唑的药物遗传学

• 批准号: 7552414
• 负责人: Danxin Wang
• 金额: $ 22.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7552414
• 关键词: AIDS/HIV problem; Accounting; Acetylation; Acquired Immunodeficiency Syndrome; Address; Adverse reactions; Affect; Affinity; Antigens; Antioxidants; Autopsy; Binding; Biological Markers; CYP2C9 gene; Candidate Disease Gene; Classification; Clinical; Condition; Cotrimoxazole; Cytochromes; DNA; Databases; Development; Distant; Drug Kinetics; Drug Metabolic Detoxication; Enzymes; Frequencies; Future; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glutathione; Goals; HLA Antigens; Hand; Haplotypes; Hepatic; Hepatic Tissue; Homeostasis; Human; Hydroxylamine; Hypersensitivity; Immune; Immune response; Immune system; Immunocompromised Host; Individual; Investigation; Lead; Light; Link; Liver; Major Histocompatibility Complex; Measurable; Measures; Mediating; Messenger RNA; Metabolic; Metabolism; Methods; Minor; Modeling; Molecular Genetics; N-acetyltransferase 1; NAT2 gene; Nature; Opportunistic Infections; Outcome; Oxidative Stress; Pathway interactions; Patients; Peroxidase; Peroxidases; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Process; Prophylactic treatment; Proteins; Public Health; Reaction; Reactive Oxygen Species; Research; Research Design; Role; Sampling; Scanning; Severities; Staging; Sulfamethoxazole; T-Lymphocyte; Testing; Tissues; Toxic effect; Trimethoprim-Sulfamethoxazole; base; cell injury; cohort; cytotoxicity; flavin-containing monooxygenase; gene interaction; genetic analysis; genetic association; novel; oxidation; prevent; protein structure; reactive oxygen intermediate; size; statistics; trait

DESCRIPTION (provided by applicant): Cotrimoxazole (Trimethoprim-sulfamethoxazole, TMP-SMX) is the agent of choice for prophylaxis against opportunistic infections associated with HIV/AIDS and other immuno-compromised states. However, hypersensitivity mediated by SMX limits its use. The goal of this project is to understand the genetic basis for variable sensitivity to SMX toxicity, an example of idiosyncratic adverse reactions observed with many drugs. Several pathways determine SMX hypersensitivity: Metabolic inactivation by N-acetyltransferases 1 and 2 (NAT1 and NAT2); metabolic oxidation to toxic hydroxylamine derivatives by CYP2C9 and other (extra-) hepatic enzymes; protection from reactive oxygen species (ROS) by the glutathione (GSH) oxidative defense system, and immune responsiveness (focus on human leukocyte antigen, HLA). Genes encoding the drug metabolizing enzymes, GSH -related enzymes, and HLA proteins are polymorphic, but the role of genetic factors in SMX hypersensitivity remains uncertain. We propose that a comprehensive approach is needed to clarify genetic factors in idiosyncratic reactions. Specific Aim 1 focuses on targeted genotyping of candidate genes (35 candidate genes and 149 polymorphisms) involved in SMX metabolism and toxicity, and in immune response (HLA) using high throughput methods. Genetic analyses will test association between genotype and clinical outcomes, comparing a cohort of HIV/AIDS patients with and without SMX hypersensitivity. To increase the power of clinical genetic association analysis, this study includes a systematic search for novel functional polymorphisms. While most of the candidate genes have been extensively studied with focus on non-synonymous SNPs that change protein structure, regulatory polymorphisms appear to be more prevalent but most remain to be discovered. Specific Aim 2 is to identify novel regulatory SNPs in NAT1 - a highly polymorphic gene - because of its important role in SMX metabolism. The approach relies on measuring allelic ratios in genomic DNA and mRNA of candidate genes in target tissues (150 liver autopsies). Any deviation from equal DNA and mRNA ratios, termed allelic expression imbalance, reveals the presence of cis-acting factors, providing a precise quantitative phenotype. Scanning the gene locus for linked SNPs reveal novel regulatory polymorphisms. Taken together, the proposed study will clarify whether genetic factors contribute to SMX hypersensitivity in HIV/AIDS patients, and identify novel functional polymorphisms in NAT1. This combined approach has promise for the general study of idiosyncratic adverse drug reactions. PUBLIC HEALTH RELEVANCE: This project aims at discovering genetic biomarkers for predicting severe adverse reactions to sulfamethoxazole, widely used in prophylaxis against opportunistic infections associated with AIDS and other immune-compromised conditions. This type of idiosyncratic adverse reactions, likely involving reactive oxygen intermediates and immune response as a causative factor, is associated with many drugs but remains poorly understood. The results of this study will assess the genetic component contributing to adverse sulfamethoxazole reaction, shed light on idiosyncratic drug reactions in general, and guide the selection of optimized therapies for individual patients.

描述（由申请人提供）： 复方新诺明（甲氧苄氨嘧啶-磺胺甲恶唑，TMP-SMX）是预防与 HIV/AIDS 和其他免疫功能低下状态相关的机会性感染的首选药物。然而，SMX 介导的超敏反应限制了其使用。该项目的目标是了解对 SMX 毒性的不同敏感性的遗传基础，这是许多药物观察到的特殊不良反应的一个例子。多种途径决定 SMX 超敏反应： N-乙酰转移酶 1 和 2（NAT1 和 NAT2）导致代谢失活； CYP2C9 和其他（额外）肝酶代谢氧化为有毒羟胺衍生物；谷胱甘肽 (GSH) 氧化防御系统对活性氧 (ROS) 的保护，以及免疫反应性（重点关注人类白细胞抗原，HLA）。编码药物代谢酶、GSH 相关酶和 HLA 蛋白的基因具有多态性，但遗传因素在 SMX 超敏反应中的作用仍不确定。我们建议需要一种综合方法来阐明特异反应中的遗传因素。具体目标 1 侧重于使用高通量方法对参与 SMX 代谢和毒性以及免疫反应 (HLA) 的候选基因（35 个候选基因和 149 个多态性）进行靶向基因分型。遗传分析将测试基因型与临床结果之间的关联，比较一组患有和不患有 SMX 超敏反应的 HIV/AIDS 患者。为了提高临床遗传关联分析的能力，本研究包括对新功能多态性的系统搜索。虽然大多数候选基因已被广泛研究，重点是改变蛋白质结构的非同义 SNP，但调控多态性似乎更为普遍，但大多数仍有待发现。具体目标 2 是鉴定 NAT1（一种高度多态性基因）中的新型调节 SNP，因为它在 SMX 代谢中发挥重要作用。该方法依赖于测量目标组织中候选基因的基因组 DNA 和 mRNA 的等位基因比率（150 例肝脏尸检）。任何偏离相等 DNA 和 mRNA 比例的偏差（称为等位基因表达失衡）都揭示了顺式作用因子的存在，从而提供了精确的定量表型。扫描基因位点以寻找相关的 SNP，揭示了新的调控多态性。总而言之，拟议的研究将阐明遗传因素是否导致 HIV/AIDS 患者对 SMX 过敏，并鉴定 NAT1 中新的功能多态性。这种组合方法有望用于特殊药物不良反应的一般研究。 公共卫生相关性：该项目旨在发现基因生物标志物，用于预测磺胺甲恶唑的严重不良反应，磺胺甲恶唑广泛用于预防与艾滋病和其他免疫受损疾病相关的机会性感染。这种类型的特殊不良反应可能涉及活性氧中间体和作为致病因素的免疫反应，与许多药物相关，但仍知之甚少。这项研究的结果将评估导致磺胺甲恶唑不良反应的遗传因素，揭示一般的特殊药物反应，并指导针对个体患者选择最佳疗法。