Genome-wide association to Staphylococcus carriage

描述（由申请方提供）：金黄色葡萄球菌是一种机会致病菌，可定植于多达1/4个体的皮肤（主要是前鼻前庭），但不会引起临床疾病症状。人类要么持续或间歇性地定植，要么从未定植过S。金黄色即，定义为载波、间歇载波或非载波。一个人的携带状态会影响他们被感染的可能性和他们对S。金黄色葡萄球菌暴露。此外，携带状态影响感染的严重程度，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S。金黄色葡萄球菌介导的疾病，但耐药菌株的数量正在迅速增加。S.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MRSA侵袭性病例94,360例，死亡18,650例（发病率31.8/10万人），远高于S. pneumoniae和H.流感。由沙门氏菌引起的感染的流行病学变化。金黄色葡萄球菌和增加的抗生素耐药性需要开发新的治疗模式。宿主对S.金黄色葡萄球菌的携带状态至少部分受潜在遗传因素的控制。查明这些问题将为制定干预战略提供目标，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以消除携带或治疗感染。我们将很快完成1000名非糖尿病和1000名2型糖尿病墨西哥裔美国人的全基因组基因分型，来自斯塔尔县，得克萨斯州使用Affyandex 6.0平台。我们最近已经试验了确定该人群携带菌株的程序，并建议确定S。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生物途径。它还将允许确定2型糖尿病和S.金黄色葡萄球菌携带/疾病易感性。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。我们将结合以计算机科学为基础的信息学和统计学方法来确定基因和区域的优先顺序，以便进行后续研究。了解这种微生物的易感性或耐药性的遗传学将显著加速和改进疫苗设计策略，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以消除携带或治疗感染。 公共卫生相关性：社区获得性S。金黄色葡萄球菌感染是一个日益严重的问题，并且越来越多的抗生素抗性菌株限制了可用的治疗选择。这项建议旨在了解与S相关的人类遗传成分。金黄色葡萄球菌携带作为鉴定与携带/疾病相关的新基因或途径的手段。这些信息可以用于开发新的治疗和预防策略。

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.