Genome-wide association to Staphylococcus carriage

描述（由申请人提供）：金黄色葡萄球菌是一种机会性病原体，可在多达1 / 4的个体中定植皮肤（主要是前鼻前庭），而不会引起临床疾病症状。人类被金黄色葡萄球菌持续或间歇定植或从未定植，即定义为携带者、间歇携带者或非携带者。一个人的携带状态影响他们成为金黄色葡萄球菌感染的可能性和他们的免疫反应的性质。此外，携带状态影响感染的严重程度，感染范围从轻微的皮肤感染到与脓肿形成、心内膜炎和肺炎相关的致命感染。某些抗生素可用于治疗金黄色葡萄球菌介导的疾病，但抗生素耐药菌株的数量正在迅速增加。金黄色葡萄球菌是现代细菌感染的最常见原因之一，部分原因是对抗生素的耐药性增加以及最近出现的由社区相关MRSA菌株（CA-MRSA）引起的感染。2005年，美国有94,360例侵袭性MRSA病例，18,650例死亡（发病率为31.8/10万人），远高于肺炎链球菌和流感嗜血杆菌。金黄色葡萄球菌引起的感染流行病学的变化和抗生素耐药性的增加需要开发新的治疗方式。宿主对金黄色葡萄球菌携带状态的易感性至少部分受到潜在遗传因素的控制。它们的鉴定将为制定干预策略提供目标，例如，鉴定与携带相关的新途径或与易感性相关的基因将允许开发新的干预措施来消除携带或治疗感染。我们将很快使用Affymetrix 6.0平台完成来自德克萨斯州斯塔尔县的1000名非糖尿病人和1000名2型糖尿病墨西哥裔美国人的全基因组基因分型。我们最近试点了确定该人群携带菌株的程序，并建议确定800名对照和600名糖尿病患者的金黄色葡萄球菌携带状态，我们将有近100万个snp和100万个拷贝数变异来进行拟议的研究。这些snp /基因的鉴定将改善风险预测，并揭示连接健康和疾病的新的生物学途径。它还将允许确定2型糖尿病和金黄色葡萄球菌携带/疾病易感性的作用/相互作用。全基因组关联研究的成功取决于创新和严格的数据分析和独立样本的复制。我们将结合基于计算机科学的信息学和统计方法来确定基因和区域的优先顺序。了解对这种生物的易感性或耐药性的遗传学将大大加快和改进疫苗设计策略，例如，确定与携带或与易感性相关的基因相关的新途径将允许开发新的干预措施来消除携带或治疗感染。

DESCRIPTION (provided by applicant): Staphylococcus aureus is an opportunistic pathogen that colonizes the skin (primarily the anterior nasal vestibule) of as many as 1 out 4 individuals without causing clinical disease symptoms. Humans are either persistently or intermittently colonized or never colonized with S. aureus i.e., defined as carriers, intermittent carriers or non-carriers. An individual's carriage status affects their likelihood of becoming infected and the nature of their immune response by S. aureus exposure. In addition, carriage status affects the severity of the infection(s) that range from minor skin infections to lethal infections associated with abscess formation, endocarditis and pneumonia. Certain antibiotics are available for the treatment of S. aureus-mediated disease, but the number of antibiotic-resistant strains is increasing rapidly. S. aureus is one of the most common causes of modern bacterial infections, in part due to increasing resistance to antibiotics and the recent emergence of infections caused by Community-Associated MRSA strains (CA-MRSA). In 2005, there were 94,360 invasive cases of MRSA in the United States, 18,650 resulted in death (incidence rate of 31.8/100,000 persons) much higher than S. pneumoniae and H. influenzae. The changing epidemiology of infections caused by S. aureus and increased antibiotic resistance necessitates the development of novel treatment modalities. Host susceptibility to S. aureus carriage status is at least partially under the control of underlying genetic factors. Their identification would provide targets for developing intervention strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections. We will shortly complete genome-wide genotyping on 1000 nondiabetic and 1000 Type-2 diabetic Mexican-Americans from Starr County, Texas using the Affymetrix 6.0 platform. We have recently piloted procedures for determining carriage strains in this population and propose to determine S. aureus carriage status for 800 of the controls and 600 of diabetes cases for whom we will have nearly 1 million SNPs and 1 million copy number variants to carry out the proposed studies. Identification of these SNPs/genes will improve risk prediction and shed light on novel biological pathways bridging health and disease. It will also allow determining the role/interaction of Type-2 diabetes and S. aureus carriage/disease susceptibility. Success of genome-wide association studies depends on innovative and rigorous data analysis and replication in independent samples. We will use a combination of computer science- based informatics and statistical methods to prioritize genes and regions for follow-up. Understanding the genetics of susceptibility or resistance to this organism shall significantly accelerate and improve vaccine design strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections. PUBLIC HEALTH RELEVANCE: Community-acquired S. aureus infections are a growing problem and the increasing number of antibiotic resistant strains is limiting available treatment options. This proposal aims to develop an understanding of the human genetic components associated with S. aureus carriage as means of identifying novel genes or pathways associated with carriage/disease. This information may then be used to develop novel treatment and prevention strategies.