Hitomi Yuki, Ebisawa Motohiro, Tomikawa Morimitsu, Imai Takanori, Komata Takatsugu, Hirota Tomomitsu, Harada Michishige, Sakashita Masafumi, Suzuki Yoichi, Shimojo Naoki, Kohno Yoichi, Fujita Kimie, Miyatake Akihiko, Doi Satoru, Enomoto Tadao, Taniguchi Masami, Higashi Noritaka, Nakamura Yusuke, Tamari Mayumi
Laboratory for Respiratory Diseases, Center for Genomic Medicine, RIKEN, Kanagawa, Japan.
J Allergy Clin Immunol. 2009 Oct;124(4):779-85.e6. doi: 10.1016/j.jaci.2009.07.044. Epub 2009 Sep 19.
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.
We sought to examine whether NLRP3 polymorphisms are associated with susceptibility to food allergy, food-induced anaphylaxis, and aspirin-induced asthma (AIA).
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.
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.
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.
含pyrin结构域的NLR家族成员3（NLRP3）通过形成炎性小体来控制炎性半胱天冬酶-1的活性，进而导致前细胞因子白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的裂解。最近的研究表明，人类NLRP3基因多态性与多种炎性疾病的易感性相关；然而，其与过敏性疾病的关联仍不明确。
我们试图研究NLRP3基因多态性是否与食物过敏、食物诱导的过敏反应以及阿司匹林诱发的哮喘（AIA）的易感性相关。
我们选择了NLRP3的15个标签单核苷酸多态性（SNP），并分别使用574例食物过敏样本和1279例AIA样本对NLRP3进行关联分析。我们还对易感SNP进行了功能分析。
两个NLRP3 SNP（rs4612666和rs10754558）与食物诱导的过敏反应易感性显著相关（P值分别为0.00086和0.00068）。这两个SNP的NLRP3单倍型也显示出显著关联（P = 0.000098）。我们能够证实其与另一种超敏反应表型AIA的易感性相关（rs4612666，P = 0.0096）。功能分析表明，rs4612666和rs10754558的风险等位基因分别增加了NLRP3表达的增强子活性和NLRP3 mRNA稳定性。
我们的结果表明，NLRP3 SNP可能以功能获得的方式在食物诱导的过敏反应和AIA的发生发展中起重要作用。对NLRP3炎性小体的进一步研究将有助于开发针对食物诱导的过敏反应和AIA的新型诊断和治疗方法。
Zotero 插件