Genetic Modifiers in CF: Role of ABH polymorphisms

描述(申请人提供)：病原体入侵宿主与宿主细胞表面糖基化模式密切相关。糖基化模式受糖基转移酶的表达和活性的调节；几种负责组织-血液(ABH)组系统的糖基转移酶也可能调节病原体结合的关键碳水化合物决定因素。因此，我们选择ABH分型作为一个关键的独立因素来检验这一假说，即糖基化模式的差异可能导致宿主-病原体相互作用的异常，从而导致囊性纤维化的疾病严重程度。几个表型特征，包括性别、营养状况和胎粪性肠梗阻(可能是回肠粘液糖化异常所致)影响肺部严重程度，也将被评估。我们将追求以下具体目标：(1)确定ABH途径基因(包括ABO、FUT2[分泌者状态]和FUT3[Lewis抗原])的多态是否与“重度”或“轻度”肺部疾病分离，或与CF病原体定植有关；(2)确定ABH途径的多态与非肺表型特征(如胎粪性肠梗阻)之间的关联。

DESCRIPTION (provided by applicant): Pathogen invasion of the host is intimately linked to patterns of glycosylation on host cell surfaces. Glycosylation patterns are regulated by the expression and activity of glycosyltransferases; several glycosyltransferases responsible for the histo-blood (ABH) group system may also regulate key carbohydrate determinants of pathogen binding. Therefore, we have chosen ABH typing as a key independent factor to test the hypothesis that differences in glycosylation patterns may lead to abnormalities in host-pathogen interactions, and thus, contribute to the severity of disease in cystic fibrosis. Several phenotypic characteristics including gender, nutritional status, and meconium ileus (which may result from abnormal glycosyation of ileal mucus) affect pulmonary severity and will also be evaluated. The following specific aims will be pursued: (1) Determine whether polymorphisms in genes in the ABH pathway (including ABO, FUT2 [Secretor status], and FUT3 [Lewis antigen]) segregate with "severe" or "mild" lung disease, or with CF pathogen colonization; (2) Determine the association between polymorphisms in the ABH pathway and nonpulmonary phenotype characteristics, such as meconium ileus.