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A1283 - TYRO3: A Gene for Allergic Rhinitis?
Author Block: J. Kanazawa1, H. Masuko1, Y. Yatagai1, H. Yamada1, T. Sakamoto1, H. Kitazawa1, H. Iijima2, T. Naito2, T. Hirota3, M. Tamari4, N. Hizawa1; 1Pulmonary Medicine, University of Tsukuba, Tsukuba, Japan, 2Tsukuba Medical Center, Tsukuba, Japan, 3Laboratory for Respiratory and Allergic Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, 4Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
Rationale: TYRO3 is a member of the TAM receptor tyrosine kinase subgroup. A recent meta-analysis of 3 independent genome-wide association studies of Latinos and African American has shown that multiple intronic variants in TYRO3 were associated with early-onset allergic asthma (Chan PY, et al. Science. 2016). The activation of TYRO3, expressed on dendritic cells, limits the magnitude of the type 2 immune response. We sought to examine the genetic contribution of expression quantitative trait loci (eQTLs) at TYRO3 gene to the development of atopy, asthma and allergic rhinitis in Japanese adults.
Methods: We performed a candidate gene case-control association study of atopy, asthma, and allergic rhinitis using 2 independent Japanese populations (a total number of 1897 adults). We defined atopy as a positive response to at least 1 of the 14 common inhaled allergens. Given that the minor allele frequency of rs1200341, which showed the strongest association with asthma in the previous meta-analysis of GWAS is very rare (0.8%) in Japanese, we initially searched eQTLs of TYRO3 using the GTEx Portal database (https://gtexportal.org/home/). We estimated the eQTLs for association with atopy, asthma and allergic rhinitis by logistic regression. In addition, the genetic effect of the eQTLs on the development of previously identified clusters of allergic sensitization (Iijima H, et al. Allergol Int. 2013) was examined using multinomial logistic regression analysis. All analyses were performed using SPSS (version 24).
Results: For genetic analysis, we selected 8 SNPs which were associated with the expression levels of TYRO3 mRNA in lung (P value less than 5x10-10) and had minor allele frequency more than 10% in a Japanese population. Among these SNPs, rs2297377 was associated with atopy and allergic rhinitis (Meta OR=1.29 and 1.31, P=0.001 and 0.001, respectively). None of the 8 SNPs were associated with the presence of asthma even when we restricted the analysis to atopic asthma. Allele G on rs2297377 is correlated with decreased expression of TYRO3, which is associated with increased risk of atopy and allergic rhinitis. Significant associations of the variant were found with two clusters: one is characterized by strongly sensitized to cedar pollen only, the other is characterized by strongly sensitized to many types of pollens (OR=1.43 and 1.61, P=0.001 and 0.03, respectively).
Conclusions: Our study identified TYRO3 as a susceptibility gene to atopy and allergic rhinitis, but not to asthma in Japanese adults.