H.Pylori Infection in Hispanic Children: Immune response pathway SNP pattterns

描述（由申请人提供）：在项目公告PA-06-183：“NIDDK疾病的健康差异”中，国家糖尿病、消化和肾脏疾病研究所（NIDDK）寻求研究，以了解和减轻其范围内高优先级疾病的健康差异问题，包括幽门螺杆菌感染，该疾病感染62%的西班牙裔，而非西班牙裔白人感染26%。持续的幽门螺杆菌感染与50%以上的消化性溃疡有关，是胃癌的一个重要危险因素。我们的目的是确定影响西班牙裔儿童幽门螺杆菌感染获得和持续的遗传和环境因素。我们将使用PASITOS (NIDDK R01-DK53664)，这是一个建立在美墨边境的低收入西班牙裔儿童出生队列，用于调查幽门螺杆菌感染的自然史。PASITOS表明，大多数在生命早期获得的幽门螺旋杆菌感染不会持续存在：因此，遗传风险因素可能决定了感染的持久性，可能与环境因素相结合。最近的研究表明，免疫反应在对幽门螺杆菌感染的易感性中起作用。toll样受体（TLR）信号转导通路调节对带有鞭毛的革兰氏阴性细菌的免疫应答，包括幽门螺杆菌。我们假设，通过单核苷酸多态性（SNPs）测量，幽门螺杆菌的定植和持久性受到TLR途径遗传变异的影响。其次，我们假设这些相同的snp改变了细菌负荷测量的效果：即家庭中的感染。了解遗传和环境因素在幽门螺杆菌感染的获得和持续中的作用，有助于确定对慢性幽门螺杆菌感染高度敏感的亚群，并确定干预的潜在分子靶点，以预防随后的胃部疾病。具体目的是：1)确定TLR信号转导通路中的snp是否影响幽门螺杆菌感染的发生率和持续性。我们将采集样本，评估TLR信号转导通路中的snp。贝叶斯方法将用于估计SNP和上位性对定植和持久性的影响。2)确定与幽门螺杆菌感染发生率和持续性相关的snp是否会改变与感染风险相关的环境因素的影响：特别是通过家庭感染水平测量的细菌负荷。与公共卫生相关：虽然幽门螺杆菌感染率在低收入的西班牙裔儿童中很高，但对于一些儿童来说，抗生素可能没有必要预防与持续感染有关的胃病。我们需要找出谁会持续感染并治疗他们。由于免疫反应和细菌暴露会影响感染，我们建议在PASITOS研究中研究相关基因和家庭感染以及它们如何相互作用以预测幽门螺杆菌感染。

DESCRIPTION (provided by applicant): In Program Announcement PA-06-183: "HEALTH DISPARITIES IN NIDDK DISEASES," The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) seeks research to understand and mitigate issues of health disparities in high priority diseases within its scope, including Helicobacter pylori infection, which infects 62% of Hispanics compared to 26% in non-Hispanic whites. Persistent H. pylori infection is associated with more than 50% of peptic ulcers and is a strong risk factor for stomach cancer. Our objective is to identify genetic and environmental factors that influence acquisition and persistence of H. pylori infection in Hispanic children. We will use PASITOS (NIDDK R01-DK53664), a birth cohort of low income Hispanic children on the US-Mexico border which was established to investigate the natural history of H. pylori infection. PASITOS demonstrated that most H. pylori infections acquired early in life do not persist: so, genetic risk factors may determine infection persistence, possibly in combination with environmental factors. Recent studies have shown that the immune response plays a role in susceptibility to H. pylori infection. The toll-like receptor (TLR) signal transduction pathway regulates immune response to gram negative bacteria with flagella, including H. pylori. We hypothesize that H. pylori colonization and persistence are influenced by genetic variation in the TLR pathway as measured by single nucleotide polymorphisms (SNPs). Secondarily, we hypothesize that these same SNPs modify the effects of measures for bacterial load: that is, infection in the household. Understanding the role of genetic and environmental factors in the acquisition and persistence of H. pylori infection could help to identify subgroups that are highly susceptible to chronic H. pylori infection and determine potential molecular targets for intervention to prevent subsequent gastric disease. Specific Aims are: 1) To determine if SNPs in the TLR signal transduction pathway influence the incidence and persistence of H. pylori infection. We will take collected samples and evaluate SNPs in the TLR signal transduction pathway. A Bayesian approach will be used to estimate SNP and epistatic effects on colonization and persistence. 2) To determine if SNPs that are associated with incidence and persistence of H. pylori infection modify the effects of environmental factors associated with infection risk: in particular, bacterial load as measured by household infection levels. RELEVANCE TO PUBLIC HEALTH: While H. pylori infection rates are high in low income Hispanic children, antibiotics might not be necessary to prevent stomach diseases linked to constant infection for some children. We need to find out who will develop constant infection and treat them. Since immune response and bacterial exposure influence infection, we propose to look at related genes and household infection and how they interact to predict H. pylori infection in the PASITOS study.