A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

Abstract

Atopic diseases are the most common chronic diseases of childhood, and the genetics of atopy are complex and heterogeneous. Protease-activated receptor-2 (PAR-2) is involved in various inflammatory diseases, but the association of PAR-2 with allergic diseases remains unclear. To examine the contribution of genetic variation of PAR-2 to atopic phenotypes in the Korean childhood cohort. We identified PAR-2 variations in a Korean population and conducted association analyses by using 316 unrelated atopic and 210 nonatopic subjects. We analyzed serum IgE and total eosinophil count levels and examined PAR-2 mRNA and protein expression levels. In the case-control association analysis, atopy was significantly associated with a single c.621C>T (p.I207I, rs631465) polymorphism of PAR-2 (P= .001, odds ratio= 1.95). Subjects with the c.621T risk allele had significantly higher serum IgE (P= .004) and total eosinophil count (P=.03) levels. Moreover, the positive association of c.621T was reproduced in the replication study (P= .01, joint Pvalue of the replication <.001). An in silico analysis of RNA secondary structure prediction revealed that the C to T conversion at c.621 greatly increased predicted PAR-2 mRNA stability. This was also confirmed by an invitro assay for mRNA stability. Furthermore, following an invivo approach on gene expression in PBMCs showed that the expression levels of PAR-2 mRNA and protein in subjects with the c.621CT or TT genotype were significantly higher than in those with the c.621CC genotype. These results indicate that the synonymous c.621C>T polymorphism in PAR-2 might be associated with the risk of atopy, potentially by altering PAR-2 gene expression.