TY - JOUR
T1 - Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma
AU - Hitomi, Yuki
AU - Ebisawa, Motohiro
AU - Tomikawa, Morimitsu
AU - Imai, Takanori
AU - Komata, Takatsugu
AU - Hirota, Tomomitsu
AU - Harada, Michishige
AU - Sakashita, Masafumi
AU - Suzuki, Yoichi
AU - Shimojo, Naoki
AU - Kohno, Yoichi
AU - Fujita, Kimie
AU - Miyatake, Akihiko
AU - Doi, Satoru
AU - Enomoto, Tadao
AU - Taniguchi, Masami
AU - Higashi, Noritaka
AU - Nakamura, Yusuke
AU - Tamari, Mayumi
PY - 2009/10
Y1 - 2009/10
N2 - Background: NLR family, pyrin domain containing 3 (NLRP3), controls the activity of inflammatory caspase-1 by forming inflammasomes, which leads to cleavage of the procytokines IL-1β and IL-18. Recent studies have shown associations of human NLRP3 polymorphisms with susceptibility to various inflammatory diseases; however, the association with allergic diseases remains unclear. Objective: We sought to examine whether NLRP3 polymorphisms are associated with susceptibility to food allergy, food-induced anaphylaxis, and aspirin-induced asthma (AIA). Methods: We selected 15 tag single nucleotide polymorphisms (SNPs) of NLRP3 and conducted association analyses of NLRP3 using 574 and 1279 samples for food allergy and AIA, respectively. We further performed functional analyses of the susceptible SNPs. Results: Two NLRP3 SNPs (rs4612666 and rs10754558) were significantly associated with susceptibility to food-induced anaphylaxis (P = .00086 and P = .00068, respectively). The NLRP3 haplotype of the 2 SNPs also showed a significant association (P = .000098). We could confirm the association with susceptibility to another hypersensitivity phenotype, AIA (rs4612666, P = .0096). Functional analysis revealed that the risk alleles of rs4612666 and rs10754558 increased the enhancer activity of NLRP3 expression and NLRP3 mRNA stability, respectively. Conclusion: Our results indicate that the NLRP3 SNPs might play an important role in the development of food-induced anaphylaxis and AIA in a gain-of-function manner. Further research on the NLRP3 inflammasome will contribute to the development of novel diagnostic and therapeutic methods for food-induced anaphylaxis and AIA.
AB - Background: NLR family, pyrin domain containing 3 (NLRP3), controls the activity of inflammatory caspase-1 by forming inflammasomes, which leads to cleavage of the procytokines IL-1β and IL-18. Recent studies have shown associations of human NLRP3 polymorphisms with susceptibility to various inflammatory diseases; however, the association with allergic diseases remains unclear. Objective: We sought to examine whether NLRP3 polymorphisms are associated with susceptibility to food allergy, food-induced anaphylaxis, and aspirin-induced asthma (AIA). Methods: We selected 15 tag single nucleotide polymorphisms (SNPs) of NLRP3 and conducted association analyses of NLRP3 using 574 and 1279 samples for food allergy and AIA, respectively. We further performed functional analyses of the susceptible SNPs. Results: Two NLRP3 SNPs (rs4612666 and rs10754558) were significantly associated with susceptibility to food-induced anaphylaxis (P = .00086 and P = .00068, respectively). The NLRP3 haplotype of the 2 SNPs also showed a significant association (P = .000098). We could confirm the association with susceptibility to another hypersensitivity phenotype, AIA (rs4612666, P = .0096). Functional analysis revealed that the risk alleles of rs4612666 and rs10754558 increased the enhancer activity of NLRP3 expression and NLRP3 mRNA stability, respectively. Conclusion: Our results indicate that the NLRP3 SNPs might play an important role in the development of food-induced anaphylaxis and AIA in a gain-of-function manner. Further research on the NLRP3 inflammasome will contribute to the development of novel diagnostic and therapeutic methods for food-induced anaphylaxis and AIA.
KW - NLR family, pyrin domain containing 3
KW - anaphylaxis
KW - aspirin-induced asthma
KW - association study
KW - enhancer activity
KW - food allergy
KW - gene polymorphism
KW - hypersensitivity
KW - mRNA stability
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U2 - 10.1016/j.jaci.2009.07.044
DO - 10.1016/j.jaci.2009.07.044
M3 - Article
C2 - 19767079
AN - SCOPUS:70449724715
VL - 124
SP - 779-785.e6
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 4
ER -