GENETIC DETERMINANTS OF LIPODYSTROPHY IN HIV-POSITIVE PATIENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。脂肪营养不良被定义为脂肪代谢的任何障碍，其不同的表现与包括艾滋病毒/艾滋病在内的许多疾病有关。这种情况被不同地称为脂肪萎缩(脂肪丢失)、脂肪重新分布或脂肪分布不均匀综合征。很明显，抗逆转录病毒治疗导致各种物理和生化变化，导致脂肪在一大批感染者中重新分布。这可能会导致尴尬和耻辱，因为它们影响患者的生活质量(QOL)。不管其复杂性或潜在影响如何，有一件事是明确的。此类并发症的发展可能严重危及患者对高效抗逆转录病毒疗法(HAART)的坚持，导致病毒载量反弹和耐药性。中心假设：不同的治疗方案是由一组有限的基因作用的，这些基因位点的变异会影响治疗方案的有效性和时程，最终影响患者的脂肪分布。拟议研究的具体目标如下：1)使用突变检测方法，从加州大学旧金山分校的数据库中筛选150名艾滋病毒阳性患者，并在UPR招募100名具有深入患者记录的艾滋病毒阳性患者，以寻找参与脂肪酸、炎症或药物代谢候选基因的8个基因的变异。假设：HIV阳性个体中存在遗传变异。2)比较人群中是否存在脂营养不良或药物治疗的多态患病率。假设：影响表型测量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来评估基因多态的功能意义，从而试图阐明基因变异影响疾病表达的机制。假设：在特定目标1和2中确定的遗传变异影响与治疗结果相关的特征测量。目前尚不清楚，为了检验关于基因变异对艾滋病毒阳性患者改变的生理和治疗参数的影响的假设，可以将药物治疗策略归类到什么程度上相关，尽管是个性化的。旨在确认发现基因变异以减轻抗病毒治疗有效性的试点研究将导致几个潜在的外部资金来源。此外，这些发现随后可以用来测试这些相同的基因变异对生活质量的影响。识别对临床结果有可测量影响的基因变异，预计也会影响生活质量。因此，在这项研究和后续研究中发现的相关基因变异不仅可以作为预测临床结果的有力工具，还可以预测生活质量。R01资助机制由国家普通医学科学研究所(NIGMS)提供，旨在促进旨在了解种族和民族群体之间的药物遗传差异的研究。或者，国家过敏和传染病研究所(NIAID)获得性免疫缺陷综合征司支持旨在确定艾滋病毒感染和疾病管理新目标的研究。拟议的试点的目的是对主要候选基因在艾滋病毒感染管理中的致病作用获得新的见解。然后，该方法可以应用于任何基因位点，以寻找艾滋病毒管理的遗传调节器

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