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Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by bronchoconstriction after ingestion of nonsteroidal anti-inflammatory drugs including aspirin. The Ca2+ concentration in bronchial epithelial cells is an important factor for bronchoconstriction. Human annexin A4 (ANXA4) is predominantly expressed in the secretory epithelia in the lung, stomach, intestine, and kidney. Furthermore, translocation and induction of ANXA4 have been observed in human Ca2+-depleted neutrophils. To investigate the association between annexin A4 polymorphisms and the risk of AERD, we have genotyped 21 variants from 102 AERD subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses controlling for sex, smoking status, and atopy as covariates were performed to estimate the association between the annexin A4 polymorphisms and AERD. Among these variants, 8 polymorphisms (rs2168116, rs4853017, rs6546547, rs13428251, rs7577864, rs7559354, rs7588022, and rs3816491) and 2 haplotypes (ANXA4-ht3 and ANXA4-ht5) were significantly associated with the risk of AERD. One common polymorphism in intron 11, rs3816491, showed the strongest association signal with susceptibility to aspirin-AERD even after multiple testing corrections (OR=0.57; 95% confidence interval 0.40-0.83; P=0.003; Pcorr=0.045 in the codominant model). Although further functional evaluations of replication studies in larger cohorts are required, our findings suggest that the annexin A4 could have susceptibility for AERD.