25 Role of Myeloid Derived Suppressor Cells in Asthma

common and potentially deleterious rare variation in this pathway would be associated with severe asthma based on SARP cluster designation. Methods: To evaluate common variants (minor allele frequency or MAF .5%), 419 SARP non-Hispanic white participants with a cluster assignment were genotyped for 182 single nucleotide polymorphisms (SNPs) in Th2 pathway genes using whole-genome SNP data. Individual SNPs and a cumulative model of significant SNPs were evaluated using contingency tables with a chisquare test for trend and ordinal regression models adjusted for age, sex, and principal components. Rare (MAF ,5%) amino acid changes and splice site alterations in this pathway were tested for association with asthma severity outcomes in 20 SARP subjects with whole exome sequence data. Results: Individual Th2 pathway variants were associated with overall SARP cluster assignment, and allergic clusters of increasing severity (1, 2, and 4), including GATA3 polymorphism rs1244186 (P 1⁄4 0.005). In an 18-SNP additive model, an increasing number of Th2 pathway risk genotypes were highly associated with severe allergic asthma (P 1⁄4 3.9 · 1026). For example, in cluster 4, the percentage of subjects with at least 9 risk genotypes was 83% compared to 35% in cluster 1. Additionally, there was evidence that subjects with rare variants in this pathway were more likely to report allergy symptoms (P 1⁄4 0.006), especially in the fall (P 1⁄4 0.003), compared to subjects with no rare variants. Conclusions: Common Th2 pathway variants predict an increased likelihood of severe allergic asthma and rare variants were associated with increased seasonal allergy symptoms.