Regulation of human immune function by 17q21 asthma risk polymorphism

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): 17q21 polymorphism is one of the strongest identified genetic risks for the development of childhood asthma. In a high risk cohort, those with the 17q21 risk TT genotype at the rs7216389 SNP who wheezed with rhinovirus as toddlers had a 90% prevalence of asthma later in childhood. One of the genes at that locus, ORMDL3, has been directly implicated in asthma pathogenesis by a transgenic mouse model. Both known functions of the endoplasmic reticulum resident ORMDL3, Serca2b calcium pump inhibition and sphingolipid synthesis inhibition, have also been implicated in asthma. Serca2b pump inhibition, and consequent calcium derangements, results in a potentially pro-inflammatory stress response known as the "Unfolded Protein Response" (UPR). The relationship between UPR and asthma pathogenesis is not clear. ORMDL3 also regulates calcium dependent functions in eosinophils. Current knowledge of ORMDL3 function derives primarily from murine models and transfected cell lines. It is not known how 17q21 polymorphisms and resulting alterations in ORMDL3 expression physiologically modulate human immune cell function. We hypothesize that 17q21 genotype regulates rhinovirus-induced ER stress responses and thus immune handling of the virus. For this proposal, we have the relatively unique opportunity of studying ORMDL3 regulated function in genotyped human eosinophils and peripheral blood mononuclear cells (PBMC). Preliminary studies investigating different cell types among PBMC revealed the greatest 17q21 genotypic differences for ORMDL3 expression in B cells. ORMDL3 was also very highly expressed in human eosinophils. Thus, in Aim 1 we will determine the effect of 17q21 polymorphism on B-cell UPR and anti-viral gene expression in response to rhinovirus stimulation. This aim will also investigate the regulation of ORMDL3, and the mechanisms by which elevated ORMDL3 alters UPR/anti-viral gene expression. In Aim 2, we will determine the consequences of 17q21 polymorphism for eosinophil calcium-dependent functions. Our preliminary data strongly support the ability to detect significant gene expression and eosinophil functional differences in 17q21 polymorphic human immune cells. Greater understanding of how 17q21 variation and associated ORMDL3 expression shape immune function may elucidate why children with risk polymorphisms are predisposed to develop asthma.