FUT2 Genotype Impact on National Burden of Norovirus Infections

描述（由申请人提供）：到五岁时，六分之一的美国儿童患有诺如病毒急性胃肠炎（age）。诺如病毒是美国儿童AGE的主要原因，由于一种新型病毒株的出现，2012年报告的病例增加了52%。本研究的目的是确定FUT2（分泌）基因对儿童AGE人群负担的贡献，特别是诺如病毒相关的AGE。FUT2基因酶控制肠道表面某些糖的产生，并被假设通过改变AGE病原体最初与宿主相互作用的表面参与AGE病原体的易感性。诺如病毒尤其与FUT2基因酶合成的糖结合。近25%的美国人缺乏功能性FUT2基因；这些人被称为“非秘书”。几项挑战研究和疫情调查表明，非分泌性病毒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索这种遗传变异对诺如病毒AGE全人群模式的影响。此外，很少有研究探索非分泌者在多大程度上仍可能传播病毒——从而可能感染他人——即使他们受到某些菌株的保护而不受症状感染。提出的研究验证了一个中心假设，即分泌基因决定了诺如病毒症状感染和无症状脱落的人群风险以及总体年龄易感性。在本研究中，在6家儿科机构进行了主动年龄监测

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