Mapping HIV/AIDS genes with haplotype-based strategies

描述（由申请人提供）：免疫应答中的遗传变异影响对感染的易感性（例如，HIV）和自身免疫性疾病，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HIV中的作用：大型流行病学队列研究已经确定了与HIV传播和进展为AIDS的速率相关的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，这表明其他基因影响发展HIV/AIDS的风险。为了研究复杂免疫系统反应的遗传调控，该资助计划系统地探索两个不同的候选基因亚组中的遗传变异，以促进HIV感染和艾滋病的进展：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，已显示β-趋化因子RANTES、MIP 1-α和MIP 1-β的水平在对HIV感染具有抵抗力的个体和那些缓慢进展为AIDS的HIV阳性患者中升高。尚未广泛研究的是，调节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。其次，先前的研究表明，与HIV/AIDS相关的两个基因HLA和CCR 5也会影响自身免疫性疾病的风险。这表明已知影响自身免疫的其他基因（例如，NOD 2/CARD 15、CTLA 4和5 q31细胞因子基因簇）也可能改变对HIV/AIDS的反应。因此，该补助金提出了两个具体目标。1)在约3500例HIV/AIDS患者的队列中，对调节RANTES、MIP 1-α和MIP 1-β产生的25个基因进行遗传关联研究;以及2）在约3500例HIV/AIDS患者的队列中，对NOD 2/CARD 15、CTLA 4和5 q31细胞因子基因簇三个位点进行遗传关联研究。这些研究希望能够发现影响艾滋病毒/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，并最终改善患者的护理。

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.