Genetic Epidemiology of HIV Risk Behavior Trajectory in the ALIVE Cohort

描述(申请人提供)：在HIV危险行为中，与静脉吸毒有关的行为最突出，静脉吸毒者的血清转换率至少为6.2%。重要的是，主要与冲动控制有关的其他行为维度是相关的，共同影响艾滋病毒感染风险，并共享潜在的神经生物学。与静脉注射体验有关的艾滋病(AIVE)是巴尔的摩从1988年开始的以社区为基础的静脉注射吸毒者的预期队列，最终招募了3500多名静脉注射吸毒者。半年一次的随访包括对危险行为和药物使用的全面评估。另一项专注于感染的非行为遗传风险的研究对样本的一个子集(N=1197)进行了全基因组关联研究(GWAS)。这将使我们能够在现有的大量、特征良好、以非裔美国人为主的样本中，在全基因组关联框架内调查所测量的基因类型对使用药物和其他行为风险衡量标准确定的艾滋病毒行为风险轨迹变异的贡献。在目标1中，我们建议在已经进行基因分型的活体样本中检查纵向静脉(IV)药物注射轨迹中类别成员的遗传贡献。在此样本之前的工作已经确定了注射毒品职业生涯中独特的纵向类别。在目标2中，我们将对一种新的“注射年限”表型进行全基因组关联扫描，旨在捕捉注射者职业生涯的长度。在目标3中，我们将使用与毒品相关的行为和性行为来生成一个新的艾滋病毒危险行为综合指数。我们将在纵向框架中检查这一新的风险度量，并执行HIV风险轨迹类别的GWA。我们的三个具体目标利用这一独特的、现有的、由NIDA资助的资源来解决关于艾滋病毒危险行为的遗传学的新假设，而不需要额外的基因分析成本。这项工作是新颖的、创新的、具有成本效益的，并可能确定对艾滋病毒风险轨迹的重要遗传贡献。检查静脉注射(IV)药物的纵向轨迹和对一种新的“注射年限”和复合艾滋病毒风险表型的活样本进行全基因组关联扫描具有重要意义，因为它将为预防和治疗战略提供信息，并有助于识别更适合预防战略的亚群或行为群。简而言之，这项研究具有重要意义，因为研究结果将澄清我们对该人群和其他人群中艾滋病毒行为风险轨迹的可改变和固定成分的理解，并导致加强治疗和预防的努力。

DESCRIPTION (provided by applicant): Among HIV risk behaviors, those related to intravenous drug use are the most salient, with sero-conversion rates among intravenous drug users of at least 6.2%. Importantly, other behavioral dimensions, primarily related to impulse control, are correlated, jointly influence HIV infection risk and share an underlying neurobiology. The AIDS Linked to the Intravenous Experience (ALIVE) is a prospective community-based cohort of intravenous drug users (IDUs) in Baltimore that commenced in 1988, eventually enrolling more than 3,500 IDUs. Semi-annual follow-up included comprehensive assessment of risk behaviors and drug use. A separate study, focused on non-behavioral genetic risk for infection performed a genome-wide association study (GWAS) on a subset (N=1197) of the sample. This will allow us, in an existing, large, well-characterized, predominantly African-American sample, to investigate in a genome-wide association framework the contribution of measured genotypes to variation in HIV behavioral risk trajectory defined using drug and other behavioral-risk measures. In Aim 1, we propose to examine the genetic contribution to class membership in longitudinal intravenous (IV) drug injection trajectories in the already genotyped ALIVE sample. Prior work in this sample has identified unique longitudinal classes of drug injection career. In Aim 2, we will perform a genome-wide association scan of a novel 'injection years' phenotype designed to capture the length of an injector's career. In Aim 3, we will generate a novel composite index of HIV-risk behavior, using drug-related and sexual behaviors. We will examine this novel risk metric in a longitudinal framework and perform a GWAS of HIV-risk trajectory class. Our three Specific Aims leverage this unique, existing, NIDA-funded resource to address novel hypotheses regarding the genetics of HIV risk behaviors without the costs of additional genetic assays. This work is novel, innovative, cost effective and likely to identify important genetic contributions to HIV risk trajectory. The examination of longitudinal intravenous (IV) drug injection trajectories and the genome-wide association scan in the ALIVE sample of a novel 'injection years' and composite HIV risk phenotypes is significant because it will inform prevention and treatment strategies and aid in identifying subpopulations or clusters of behaviors that are more amenable to prevention strategies. In short, the research is significant because the results will elucidate our understanding of modifiable and fixed components of HIV behavior risk trajectories in this and other populations, and leads to enhanced efforts at treatment and prevention.