成人发作的静动病(AOSD),一种自身炎症性疾病,与含NLR3的pyrin结构域(NLRP3)-炎性体信号的失调有关。我们旨在研究NLRP3-炎性体信号的遗传多态性与AOSD易感性和结果的关联,并检查其功能特性。使用SequenomMassArray对来自66名AOSD患者和128名健康对照的样品进行了涉及NLRP3炎症小体反应的53个候选单核苷酸多态性(SNP)的基因分型。通过使用TaqManSNP分析仪直接测序来验证显著的SNP。通过ELISA检查相关基因产物的血清水平。通过使用MassArray和随后的复制验证,确定了CARD8基因的一个SNPrs11672725与AOSD易感性显着相关(p=3.57×10-7;比值比3.02)。功能测定显示,AOSD患者的血清CARD8水平显着降低(中位数,10,524.6pg/mL)与对照组(13,964.1pg/mL,p=0.005),而患者的caspase-1,IL-1β和IL-18水平显着升高(107.1pg/mL,2.1pg/mL,和1495.8pg/mL,分别)比对照组(99.0pg/mL,1.0pg/mL,和141.4pg/mL,分别)。携带rs11672725CC基因型的患者血清caspase-1和IL-18水平(121.3pg/mL和1748.6pg/mL)明显高于CT/TT基因型的患者(72.6pg/mL,p=0.019和609.3pg/mL,p=0.046)。rs11672725CC基因型的患者中有较高比例的疾病结局的系统性模式,这与低CARD8水平有关。一种新颖的变体,CARD8基因的rs11672725被鉴定为AOSD的潜在遗传风险。携带rs11672725CC基因型和C等位基因的患者CARD8水平较低,并且倾向于全身模式,炎症小体信号表达升高。
Adult-onset Still\'s disease (AOSD), an autoinflammatory disorder, is related to the dysregulation of NLR3-containing a pyrin domain (NLRP3)-inflammasome signaling. We aimed to investigate the associations of genetic polymorphisms of NLRP3-inflammasome signaling with AOSD susceptibility and outcome and to examine their functional property. Fifty-three candidate single-nucleotide polymorphisms (SNPs) involved in NLRP3-inflammasome response were genotyped using Sequenom MassArray on the samples from 66 AOSD patients and 128 healthy controls. The significant SNPs were validated by direct sequencing using a TaqMan SNP analyzer. Serum levels of associated gene products were examined by ELISA. One SNP rs11672725 of
CARD8 gene was identified to be significantly associated with AOSD susceptibility by using MassArray and subsequent replication validation (p = 3.57 × 10-7; odds ratio 3.02). Functional assays showed that serum
CARD8 levels were significantly lower in AOSD patients (median, 10,524.6 pg/mL) compared to controls (13,964.1 pg/mL, p = 0.005), while levels of caspase-1, IL-1β and IL-18 were significantly higher in patients (107.1 pg/mL, 2.1 pg/mL, and 1495.8 pg/mL, respectively) than those in controls (99.0 pg/mL, 1.0 pg/mL, and 141.4 pg/mL, respectively). Patients carrying rs11672725CC genotype had significantly higher serum caspase-1 and IL-18 levels (121.3 pg/mL and 1748.6 pg/mL) compared to those with CT/TT genotypes (72.6 pg/mL, p = 0.019 and 609.3 pg/mL, p = 0.046). A higher proportion of patients with rs11672725CC genotype had a systemic pattern of disease outcome, which was linked to low
CARD8 levels. A novel variant, rs11672725, of the
CARD8 gene was identified as a potential genetic risk for AOSD. Patients carrying the rs11672725CC genotype and C allele had low
CARD8 levels, and were predisposed to a systemic pattern with an elevated expression of inflammasome signaling.