Genetic Predictors of Cognition in HIV+ Women

描述（由申请人提供）：本申请提出了一个博士前培训计划，旨在确定人类免疫缺陷病毒（HIV）的认知能力和脑功能障碍的遗传预测因子。该培训计划涉及三个主要领域的指导，教学和体验式研究培训：1）艾滋病毒，2）功能性磁共振成像（fMRI）和3）心理遗传学。候选人的目标是建立在功能磁共振成像和遗传学以前的培训，并进行论文项目，在一个新的方向联合这两种方法。该项目将是实现申请人职业目标的重要一步，独立研究与遗传标记有关的认知和心理健康。在这一更广泛的目标范围内，拟议的研究培训计划的总体目标是表征儿茶酚-O-甲基转移酶（COMT）基因Val 158 Met的常见多态性对中年女性艾滋病毒感染者认知和脑功能的影响。在这种特定疾病中检查这种特定基因型的动机来自于在健康成人中受COMT影响的特定认知和神经机制的大量重叠，以及在HIV患者中受损。假设是这种多态性复合了这种疾病的认知脆弱性。数据表明，Val 158 Met多态性损害前额介导的认知和生理反应。瓦尔等位基因与工作记忆任务中前额叶皮层的异常激活和加工效率降低有关。该项目旨在研究Val 158 Met多态性对中年女性艾滋病毒感染者执行功能和前额叶皮质功能障碍的影响。数据将包括来自芝加哥妇女机构间艾滋病毒研究（WIHS）网站的参与者。行为数据将包括N-back上的表现，并将在约240名女性的常规WIHS研究访视期间收集。我们预测与瓦尔/Met和Met/Met基因型相比，瓦尔/瓦尔基因型的认知表现更差，并且与HIV-对照相比，瓦尔/瓦尔基因型的负面影响在HIV+女性中更明显。为了研究这种遗传脆弱性的神经基质，18名HIV阳性女性将在N-back测试期间接受fMRI评估。据预测，与没有该等位基因的女性相比，瓦尔等位基因携带者在N-back期间将显示出增加的前额叶皮层活动。这项研究将首次评估COMT瓦尔158 Met多态性与HIV人群认知能力之间的关系。 公共卫生相关性：这些发现将为HIV阳性女性认知功能的遗传预测提供深入了解，并将有助于确定可能导致该疾病执行功能缺陷的风险因素。

DESCRIPTION (provided by applicant): This application proposes a predoctoral training program aimed at identifying genetic predictors of cognitive performance and brain dysfunction in Human Immunodeficiency Virus (HIV). The training program involves mentored, didactic, and experiential research training in three primary areas: 1) HIV, 2) functional magnetic resonance imaging (fMRI) and 3) psychogenetics. The candidate aims to build on previous training in fMRI and genetics and to conduct a dissertation project that unites the two methods in a novel direction. The project would be an important step in achieving the applicant's career goal to independently research cognition and mental health in relation to genetic markers. Within this broader goal, the general aim of the proposed research training program is to characterize the effect of a common polymorphism of the catechol- O-methyl transferase (COMT) gene, Val158Met, on cognition and brain function in midlife women with HIV. The motivation for examining this particular genotype in this particular disease comes from the large overlap in the specific cognitive and neural mechanisms shown to be affected by COMT in healthy adults and to be impaired in individuals with HIV. The hypothesis is that this polymorphism compounds the cognitive vulnerabilities that characterize this disease. Data suggests that the Val158Met polymorphism impairs prefrontal-mediated cognition and physiological response. The Val allele has been associated with abnormal activation and decreased processing efficiency of the prefrontal cortex during working memory tasks. The proposed project aims to examine the effect of the Val158Met polymorphism on executive function and prefrontal cortex dysfunction in midlife women with HIV. Data will be included from participants of the Chicago site of the Women's Interagency HIV Study (WIHS). Behavioral data will include performance on the N-back and will be collected in approximately 240 women during their routine WIHS study visits. We predict worse cognitive performance with the Val/Val genotype compared with Val/Met and Met/Met genotypes, and that the negative effect of Val/Val genotype would be more pronounced in HIV+ women compared to HIV- controls. To investigate the neural substrates of this genetic vulnerability, 18 HIV+ women will undergo fMRI assessments during performance of an N-back test. It is predicted that Val allele carriers will show increased prefrontal cortex activity during the N-back compared to women without the allele. This study will be the first to evaluate relationships between the COMT Val 158Met polymorphism and cognition in an HIV population. PUBLIC HEALTH RELEVANCE: The findings will provide insight into genetic predictors of cognitive function in HIV+ women and will help identify a risk factor that may compound executive function deficits in the disease.