FUT2 Genotype Impact on National Burden of Norovirus Infections

描述（由申请人提供）：到5岁时，每6名美国儿童中就有1名患有诺如病毒急性胃肠炎（AGE）。诺如病毒是美国儿科AGE的主要原因，由于一种新型毒株的出现，2012年报告的病例增加了52%。本研究的目的是确定FUT 2（分泌）基因对儿童AGE，特别是诺如病毒相关AGE的人群负担的贡献。FUT 2基因酶控制某些糖在肠道表面的生产，并被假设为通过修饰表面参与AGE病原体的易感性，其中AGE病原体首先与宿主相互作用。诺如病毒特别与FUT 2基因酶合成的糖结合。近25%的美国人缺乏功能性FUT 2基因，这些人被称为“非分泌型”。“一些挑战性研究和爆发调查表明，非分泌型对某些诺如病毒株的感染具有抵抗力。然而，这种关联并不适用于所有毒株，迄今为止还没有研究探讨这种遗传变异对诺如病毒AGE群体模式的影响。此外，很少有研究探索非分泌型病毒仍然可能传播病毒的程度-从而可能感染他人-即使他们受到某些菌株的保护而不会出现症状感染。这项研究验证了核心假设，即分泌遗传学决定了诺如病毒有症状感染和无症状脱落的人群风险以及总体AGE易感性。在这项研究中，在六个儿科机构进行了主动AGE监测 在全国范围内与疾病控制和预防中心（CDC）的新疫苗监测网络（NVSN）合作。从2011年12月至2012年11月，收集了1505例AGE病例和827例健康对照儿童的粪便（用于病原体检测）和唾液（用于DNA基因分型）。基于初步分析的预测显示，这些病例中至少有300例为诺如病毒阳性，包括大量被2012年新出现的诺如病毒株感染的病例。拟议的研究有两个具体目标：（1）通过国家监测网络确定FUT 2（分泌者）基因型与儿童AGE风险之间的关联;（2）比较分泌者与非分泌者中诺如病毒的无症状脱落。这项工作具有直接

DESCRIPTION (provided by applicant): By age five, 1 in 6 U.S. children have had a case of medically attended norovirus acute gastroenteritis (AGE). Norovirus is the leading cause of U.S. pediatric AGE, with reported cases rising 52% in 2012 due to the emergence of a novel strain. The purpose of this study is to determine the contribution of the FUT2 (secretor) gene to the population burden of pediatric AGE, particularly norovirus-associated AGE. The FUT2 gene enzyme controls the production of certain sugars at the gut surface, and is hypothesized to be involved in AGE pathogen susceptibility by modifying the surface where AGE pathogens first interact with the host. Noroviruses in particular bind to the sugars synthesized by FUT2 gene enzymes. Nearly 25% of the U.S. population lacks a functional FUT2 gene; these individuals are known as "non- secretors." Several challenge studies and outbreak investigations have shown that non-secretors are resistant to infection by certain strains of noroviruses. However, this association does not hold for all strains, and no studies to date have explored the impact of this genetic variant on population-wide patterns of norovirus AGE. Additionally, few studies have explored the extent to which non-secretors may still shed the virus- thus potentially infecting others- even if they are protected from symptomatic infection by certain strains. The proposed research tests the central hypothesis that secretor genetics determines the population risk of norovirus symptomatic infection and asymptomatic shedding as well as overall AGE susceptibility. For this study, active AGE surveillance was conducted at six pediatric institutions across the country in affiliation with the New Vaccine Surveillance Network (NVSN) of the Centers for Disease Control and Prevention (CDC). Stool (for pathogen testing) and saliva (for DNA genotyping) were collected from 1505 AGE cases and 827 healthy control children under the age of five from December 2011- November 2012. Projections based on preliminary analyses show that at least 300 of these cases will be norovirus positive, including a significant number of cases infected by the 2012 emerging norovirus strain. The proposed research has two specific aims: (1) Determine the association between FUT2 (secretor) genotype and risk of pediatric AGE detected through a national surveillance network and (2) Compare asymptomatic shedding of norovirus in secretors vs. non-secretors. This work has direct