Mapping HIV/AIDS genes with haplotype-based strategies

说明(申请人提供)：免疫反应中的遗传变异影响感染(例如艾滋病毒)和自身免疫性疾病的易感性，突出了在区分对外来抗原的反应和对自身抗原的耐受性方面的微妙平衡。基因变异和免疫反应之间最重要的临床关系之一涉及宿主因素在艾滋病毒中的作用：大型流行病学队列研究已经确定了10个常见的等位基因(8个基因)，它们与艾滋病毒的传播和艾滋病的进展速度有关。然而，这些等位基因只解释了艾滋病毒临床异质性的一小部分，这表明额外的基因影响发展为艾滋病毒/艾滋病的风险。为了研究复杂免疫系统反应的遗传调控，这项拨款建议系统地探索导致艾滋病毒感染和艾滋病进展的两个不同候选基因亚组的遗传变异：调节β-趋化因子产生的基因和与自身免疫性疾病相关的基因。首先，已经证明，在对艾滋病毒感染具有抵抗力的个体和那些进展缓慢的艾滋病毒阳性患者中，β-趋化因子RANTES、MIP1-α和MIP1-β的水平升高。尚未被广泛研究的是，调控β-趋化因子产生的基因内的遗传变异是否会导致艾滋病毒/艾滋病的临床异质性。其次，先前的研究表明，与艾滋病毒/艾滋病相关的两个基因，即人类白细胞抗原和CCR5，也会影响自身免疫性疾病的风险。这表明，其他已知的影响自身免疫的基因(如NOD2/CARD15、CTLA4和5q31细胞因子基因簇)也可能改变对HIV/AIDS的反应。因此，这笔赠款提出了两个具体目标。1)在大约3500名HIV/AIDS患者中与25个调节RANTES、MIP1-α和MIP1-β产生的基因进行遗传关联研究；以及2)在大约3500名HIV/AIDS患者中与NOD2/CARD15、CTLA4和5q31细胞因子基因簇进行遗传关联研究。这些研究希望确定影响艾滋病毒/艾滋病易感性的新基因，从而为艾滋病毒/艾滋病的发病机制提供洞察，并最终改善患者护理。

DESCRIPTION (provided by applicant): Genetic variation in the immune response influences susceptibility to infection (e.g., HIV) and autoimmune diseases, highlighting a delicate balance in discriminating between response to foreign antigen and tolerance to self antigens. One of the most clinically important relationships between gene variation and the immune response involves the role of host factors in HIV: large epidemiological cohort studies have identified ten common alleles (eight genes) that are associated with transmission of HIV and rate of progression to AIDS. These alleles explain only a small fraction of the clinical heterogeneity in HIV, however, suggesting that additional genes influence the risk of developing HIV/AIDS. To study genetic regulation of complex immune system responses, this grant proposes to systematically explore genetic variation in two distinct subgroups of candidate genes for a contribution to HIV infection and progression to AIDS: genes that regulate the production of beta-chemokines and genes associated with autoimmune disease. First, levels of the beta-chemokines RANTES, MIP1-alpha, and MIP1-beta have been shown to be elevated in individuals resistant to HIV infection and those HIV-positive patients who progress slowly to AIDS. What has not been extensively studied is whether genetic variation within genes regulating the production of beta-chemokines may contribute to the clinical heterogeneity of HIV/AIDS. Second, prior studies have shown that two genes associated with HIV/AIDS, HLA and CCR5, also influence risk of autoimmune disease. This suggests that other genes known to influence autoimmunity (e.g., NOD2/CARD15, CTLA4, and the 5q31 cytokine gene cluster) might also alter response to HIV/AIDS. Thus, this grant proposes two Specific Aims. 1) To perform genetic association studies with 25 genes that regulate the production of RANTES, MIP1-alpha, and MIP1-beta in a cohort of approximately 3500 HIV/AIDS patients; and 2) To perform genetic association studies with three loci, NOD2/CARD15, CTLA4, and 5q31 cytokine gene cluster, in a cohort of approximately 3500 HIV/AIDS patients. These studies hope to identify novel genes that influence susceptibility to HIV/AIDS, thereby providing insight into HIV/AIDS pathogenesis and, ultimately, improving patient care.