GENETIC DETERMINANTS OF LIPODYSTROPHY IN HIV-POSITIVE PATIENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。脂肪营养不良被定义为任何脂肪代谢紊乱，其不同表现与许多疾病有关，包括艾滋病毒/艾滋病。这种情况被称为脂肪萎缩（脂肪减少）、脂肪再分配或脂肪分布失调综合征。很明显，抗逆转录病毒治疗在很大一部分受感染个体中导致多种物理和生化变化，导致脂肪重新分布。这可能会导致尴尬和耻辱，因为它们会影响患者的生活质量（QOL）。不管并发症或潜在影响如何，有一点是明确的。这些并发症的发生可能严重危及患者对高效抗逆转录病毒治疗（HAART）方案的坚持，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起作用的，这些基因位点的变异影响治疗方案的有效性和时间过程，最终影响患者的脂肪分布。本研究的具体目的如下：1)利用突变检测方法，从UCSF数据库中筛选150名hiv阳性个体，并在UPR中招募100名具有深度患者记录的hiv阳性个体，以检测参与脂肪酸、炎症或药物代谢候选基因的8个基因的变异。假设：遗传变异存在于hiv阳性个体群体中。2)比较二分类人群中存在脂肪营养不良或药物治疗方案时的多态性患病率。假设：不同的等位基因频率存在于影响表型测量的候选基因中。3)通过生理指标的相关性来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：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性状测量。尽管个性化的药物治疗策略可以分组，但目前尚不清楚相关程度如何，以便测试有关遗传变异对艾滋病毒阳性个体生理和治疗参数改变的影响的假设。旨在确认检测降低抗病毒治疗有效性的遗传变异的潜力的试点研究将带来几个潜在的校外资金来源。此外，这些发现可以随后用于测试这些相同的遗传变异对生活质量的影响。确定对临床结果有可衡量影响的遗传变异，预计也会影响生活质量。因此，在本研究和后续研究中发现的相关遗传变异不仅可以作为临床结果的有力预测工具，还可以作为生活质量的预测工具。国家普通医学科学研究所（NIGMS）提供了R01资助机制，旨在促进旨在了解种族和族裔群体之间药物遗传差异的研究。另外，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管理艾滋病毒感染和疾病的新靶点的研究。拟议试点的目的是获得新的见解，主要候选基因在hiv感染管理的致病作用。然后，该方法可以应用于寻找艾滋病毒管理的遗传调节剂的任何基因位点

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