Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma.
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-1beta 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.


CONCLUSIONS
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.
Hitomi
Yuki
Y
Laboratory for Respiratory Diseases, Center for Genomic Medicine, RIKEN, Kanagawa, Japan.
Ebisawa
Motohiro
M
Tomikawa
Morimitsu
M
Imai
Takanori
T
Komata
Takatsugu
T
Hirota
Tomomitsu
T
Harada
Michishige
M
Sakashita
Masafumi
M
Suzuki
Yoichi
Y
Shimojo
Naoki
N
Kohno
Yoichi
Y
Fujita
Kimie
K
Miyatake
Akihiko
A
Doi
Satoru
S
Enomoto
Tadao
T
Taniguchi
Masami
M
Higashi
Noritaka
N
Nakamura
Yusuke
Y
Tamari
Mayumi
M
D000483:Alleles; D000707:Anaphylaxis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001241:Aspirin / Q000009:adverse effects*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020641:Polymorphism, Single Nucleotide
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D001241:Aspirin