GENETIC DETERMINANTS OF LIPODYSTROPHY IN HIV-POSITIVE PATIENTS

HIV 阳性患者脂肪营养不良的遗传决定因素

• 批准号: 7381030
• 负责人: JOSE F RODRIGUEZ-ORENGO
• 金额: $ 2.02万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381030
• 关键词: GENETIC; DETERMINANTS; LIPODYSTROPHY; HIV; POSITIVE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lipodystrophy is defined as any disturbance of fat metabolism, varying manifestations of which are associated with many medical conditions, including HIV/AIDS. The condition is variably referred to as lipoatrophy (loss of fat), fat redistribution or fat maldistribution syndrome. It is clear is that anti-retroviral therapy results in a variety of physical and biochemical changes leading to fat redistribution in a large subset of infected individuals. This may cause embarrassment and stigma as they impact a patient's quality of life (QOL). Regardless of the complication or its potential effect, one thing is clear. The development of such complications can seriously jeopardize patient adherence to highly active antiretroviral therapy (HAART) regimens, resulting in viral load rebound and resistance. Central hypothesis: Varying treatment regimens are acted upon by a limited set of genes and that variation at these gene loci impacts the effectiveness and time-course of treatment regimens, and ultimately the patients' fat distribution. The specific aims of the proposed research are as follows: 1) To screen 150 HIV-positive individuals from a UCSF database and 100 to be recruited at UPR with in-depth patient records for variations in 8 genes participating in fatty acid, inflammation, or drug metabolism candidate genes using mutation detection methodologies. Hypothesis: Genetic variation exists within a population of HIV-positive individuals. 2) To compare the polymorphism prevalence when the population is dichotomized with respect to presence of lipodystrophy or drug regimen. Hypothesis: Disparate allele frequencies exist in candidate genes that influence phenotypic measures. 3) To assess the functional significance of the polymorphisms through correlation of physiologic measures, thereby attempting to elucidate the mechanisms by which genetic variation affects disease expression. Hypothesis: The genetic variations identified in specific aims 1 and 2 influences the trait measures associated with treatment outcomes. It is as yet unclear to what extent related, though individualized, drug treatment strategies could be grouped in order to test hypotheses concerning the impact of genetic variation on physiologic and treatment parameters altered in HIV-positive individuals. Pilot studies aimed at affirming the potential to detect genetic variations that mitigate the effectiveness of antiviral therapy would lead to several potential extramural funding sources. Moreover, these findings can subsequently be used to test the impact of these same genetic variations on QOL. Identifying genetic variations, which have a measurable impact on clinical outcomes, would be expected to also impact QOL. Thus, relevant genetic variations identified in this and subsequent studies could represent powerful prognostic tools for not only clinical outcomes, but also quality of life. An R01 funding mechanism is offered by the National Institute of General Medical Sciences (NIGMS), which fosters research aimed at understanding pharmacogenetic differences among racial and ethnic groups. Alternatively, the National Institute of Allergy and Infectious Diseases (NIAID), Division of Acquired Immunodeficiency Syndromes support research aimed at identifying novel targets for management of HIV-infection and disease. The objective of the proposed pilot is to gain new insight into the etiopathogenic roles of prime candidate genes in management of HIV-infection. The methodology can then be applied to any gene locus in the search for genetic modulators of HIV management

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。脂肪营养不良的定义为脂肪代谢的任何干扰，其各种表现与许多医疗状况（包括HIV/AIDS）有关。该疾病被多样化地称为脂肪肉芽（脂肪损失），脂肪再分配或脂肪麦迪分布综合征。很明显，抗逆转录病毒疗法会导致各种物理和生化变化，从而导致大量感染个体的脂肪再分配。这可能会导致尴尬和污名，因为它们会影响患者的生活质量（QOL）。不管并发症或潜在效果如何，一件事很明显。这种并发症的发展会严重危害患者对高度活跃的抗逆转录病毒疗法（HAART）方案的依从性，从而导致病毒载荷反弹和耐药性。 中央假设：不同的治疗方案由有限的基因作用，这些基因基因座的变异会影响治疗方案的有效性和时间顺序，并最终影响患者的脂肪分布。 拟议研究的具体目的如下：1）从UCSF数据库中筛选150个HIV阳性个体，并在UPR中招募100个患者，并使用突变方法检测方法的8个基因中的深入患者记录，用于8种参与脂肪酸，炎症或药物代谢候选基因的变化。假设：遗传变异存在于HIV阳性个体的人群中。 2）比较当种群相对于存在脂肪营养不良或药物方案的人群时，多态性的流行率。假设：影响表型措施的候选基因中存在不同的等位基因频率。 3）通过生理指标的相关性评估多态性的功能意义，从而试图阐明遗传变异影响疾病表达的机制。假设：特定目的1和2中确定的遗传变异影响了与治疗结果相关的特征测量。 目前尚不清楚，尽管可以分组个性化的药物治疗策略，以测试有关遗传变异对HIV阳性个体改变的生理和治疗参数的影响的假设。试点研究旨在确认检测遗传变异以减轻抗病毒疗法的有效性的潜力将导致几种潜在的壁外资金来源。此外，这些发现随后可以用来测试这些相同遗传变异对质量的影响。鉴定遗传变异对临床结果产生可测量的影响，也有望影响QOL。因此，在此和随后的研究中确定的相关遗传变异可能不仅可以为临床结果，而且还代表着强大的预后工具，而且还可以代表生活质量。美国国家一般医学科学研究所（NIGMS）提供了R01资金机制，该研究所促进了旨在了解种族和族裔之间的药物遗传学差异的研究。另外，美国国家过敏和传染病研究所（NIAID），可获得的免疫缺陷综合症的划分支持研究，旨在确定用于管理HIV感染和疾病的新目标。提出的试点的目的是获得对主要候选基因在HIV感染管理中的病情病作用的新见解。然后，该方法可以应用于寻找HIV管理的遗传调节剂的任何基因基因座