Mapping HIV/AIDS genes with haplotype-based strategies

描述（由申请人提供）：免疫反应的遗传变异影响对感染（如HIV）和自身免疫性疾病的易感性，突出了对外来抗原的反应和对自身抗原的耐受性之间的微妙平衡。基因变异与免疫反应之间最重要的临床关系之一涉及宿主因子在艾滋病毒中的作用：大型流行病学队列研究已经确定了与艾滋病毒传播和艾滋病进展率相关的10个常见等位基因（8个基因）。然而，这些等位基因只能解释HIV临床异质性的一小部分，这表明其他基因会影响HIV/AIDS的发病风险。为了研究复杂免疫系统反应的遗传调控，该基金建议系统地探索两个不同的候选基因亚群的遗传变异，这些基因对HIV感染和艾滋病的进展有贡献：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，β趋化因子RANTES、mip1 - α和mip1 - β的水平在对HIV感染有抵抗力的个体和进展缓慢的HIV阳性患者中升高。调控β趋化因子产生的基因内的遗传变异是否可能导致HIV/AIDS的临床异质性，这一点尚未得到广泛研究。其次，先前的研究表明，HLA和CCR5这两个与HIV/AIDS相关的基因也会影响自身免疫性疾病的风险。这表明其他已知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，该基金提出了两个具体目标：1)在大约3500名HIV/AIDS患者中，对25个调控RANTES、mip1 - α和mip1 - β产生的基因进行遗传关联研究；2)在约3500名HIV/AIDS患者队列中进行NOD2/CARD15、CTLA4和5q31细胞因子基因簇三个基因座的遗传关联研究。这些研究希望确定影响艾滋病毒/艾滋病易感性的新基因，从而深入了解艾滋病毒/艾滋病的发病机制，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.