HLA Fine Mapping to Elucidate S. aureus Susceptibility

这个应用程序使用大量的人类预期队列来确定宿主的遗传决定因素。 对金黄色葡萄球菌菌血症(SAB)的易感性，这是一种常见的潜在致命感染。这个 在这项研究中要检验的首要假设是人类白细胞抗原中的特定变体 (人类白细胞抗原)II类区域是人类对SAB易感性的重要决定因素，这些 决定因素可以通过研究大量的、特征良好的患者队列来确定。这一假设是 基于我们分别进行的两项研究，这两项研究1)确定了人类白细胞抗原变异在全基因组范围内的显著关联 第二类，在欧洲人后裔中感染金黄色葡萄球菌的风险增加；以及2)发现 非裔美国人患者中来自欧洲的人类白细胞抗原II类变异与SAB的全基因组关联。在……里面 在这项拟议的研究中，我们将进一步提炼人类白细胞抗原II类区域SAB的遗传危险因素。我们创造了 金黄色葡萄球菌菌血症集团(SABG)是世界上最大的配对人类DNA和 沙门氏菌病患者的血液细菌。我们组建了一支经验丰富的多学科团队，将 独特的SABG队列资源，以最先进的基因分型技术和创新的体内模型系统， 突破领域的界限。我们提出了三个具体目标。在目标1中，我们将确定遗传风险 用高密度基因分型和归因法饱和人类白细胞抗原II类与SAB发病的因素 2300名患有SAB的患者和2300名未受影响的对照人群参加了纵向前瞻性研究 SABG队列。在目标2中，我们将研究人类白细胞抗原II类等位基因和单倍型与 2300例SA1基因分型的SAB患者并发SAB及细菌影响 通过对所有金黄色葡萄球菌血液分离株进行基因分型，对并发SAB的风险进行基因分型 2300例SAB患者。通过这种方法，我们将检验复杂的SAB是否与人类白细胞抗原II类的相关性 等位基因和单倍型受到金黄色葡萄球菌特定遗传谱系的影响。在目标3中，我们 将评估在目标1、目标2和我们之前的研究中确定的人类白细胞抗原等位基因的功能后果 通过体内和体外实验进行研究。我们将评估特定的人类白细胞抗原II类等位基因是否显著 利用1)金黄色葡萄球菌败血症转基因小鼠模型改变宿主T细胞对金黄色葡萄球菌的反应 2)金黄色葡萄球菌感染抗原对SAB患者T细胞的刺激 呈现细胞表达不同的人类白细胞抗原等位基因。该项目的长期目标是：1)充分 在SAB患者和未受影响的对照组的多种族样本中表征人类白细胞抗原变异；以及2) 为本项目中确定的人类白细胞抗原II类变异的临床相关性提供生物学证据。已被占用 总之，这项提议的影响是增加我们对宿主遗传变异如何影响的理解 金黄色葡萄球菌感染的开始和严重程度。阐明金黄色葡萄球菌易感性的遗传基础 感染将提高我们对这一紧急的、未得到满足的医疗危机的理解、治疗和预防。

This application uses a large human prospective cohort to identify the host genetic determinants of susceptibility to Staphylococcus aureus bacteremia (SAB), a common and potentially lethal infection. The overarching hypothesis to be tested in this study is that specific variants in the Human Leukocyte Antigen (HLA) class II region are important determinants of susceptibility to SAB in humans, and that these determinants can be identified by studying large, well-characterized cohorts of patients. This hypothesis is based upon our two separate studies that 1) identified genome-wide significant associations of variants in HLA class II with an increased risk for S. aureus infections in individuals of European descent; and 2) identified a genome-wide association of European-derived HLA Class II variants and SAB in African-American patients. In the proposed study, we will further refine the genetic risk factors for SAB in the HLA class II region. We created the S. aureus Bacteremia Group (SABG), one of the world’s largest collections of paired human DNA and bloodstream bacteria from patients with SAB. We assembled an experienced multidisciplinary team to link the unique SABG cohort resources to state-of-the-art genotyping technology and innovative in vivo model systems, pushing the boundaries of the field. We propose three Specific Aims. In Aim 1, we will identify the genetic risk factors in HLA class II for developing SAB, using high-density genotyping and imputation to saturate the HLA region in 2300 individuals with SAB and 2300 unaffected controls enrolled in the longitudinal, prospective SABG cohort. In Aim 2, we will examine the association of HLA class II alleles and haplotypes with complicated SAB in the 2300 patients with SAB genotyped in SA1, and consider the impact of bacterial genotype on the risk for complicated SAB by genotyping the bloodstream S. aureus isolates from all of the 2300 SAB patients. In this way, we will test whether the association of complicated SAB with HLA class II alleles and haplotypes is modified by the specific genetic lineage of the bloodstream S. aureus. In Aim 3, we will evaluate the functional consequences of the HLA alleles identified in Aim 1, Aim 2, and in our previous studies with in vivo and in vitro experiments. We will evaluate whether specific HLA class II alleles significantly alter host T cell responses to S. aureus using 1) a S. aureus sepsis model in transgenic mice expressing human HLA class II alleles; and 2) stimulation of T cells from SAB patients using S. aureus infected antigen presenting cells expressing different HLA alleles. The long-term objectives of this project are 1) to fully characterize HLA variation in a multi-ethnic sample of individuals with SAB and unaffected controls; and 2) to provide biological evidence for the clinical relevance of the HLA class II variants identified in this project. Taken together, the impact of this proposal is to increase our understanding of how host genetic variation influences the initiation and severity of S. aureus infections. Elucidating the genetic basis of susceptibility to S. aureus infection will improve our understanding, treatment, and prevention of this urgent unmet medical crisis.