Association of NLRP1 Coding Polymorphism with Lung Function and Serum IL-1β Concentration in Patients Diagnosed with Chronic Obstructive Pulmonary Disease (COPD)

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by a progressive decline in lung function due to airflow limitation, mainly related to IL-1β-induced inflammation. We have hypothesized that single nucleotide polymorphisms (SNPs) in <i>NLRP</i> genes, coding for key regulators of IL-1β, are associated with pathogenesis and clinical phenotypes of COPD. We recruited 704 COPD individuals and 1238 healthy controls for this study. Twenty non-synonymous SNPs in 10 different <i>NLRP</i> genes were genotyped. Genetic associations were estimated using logistic regression, adjusting for age, gender, and smoking history. The impact of genotypes on patients' overall survival was analyzed with the Kaplan-Meier method with the log-rank test. Serum IL-1β concentration was determined by high sensitivity assay and expression analysis was done by RT-PCR. Decreased lung function, measured by a forced expiratory volume in 1 s (FEV₁% predicted), was significantly associated with the minor allele genotypes (AT + TT) of <i>NLRP1</i> rs12150220 (<i>p</i> = 0.0002). The same rs12150220 genotypes exhibited a higher level of serum IL-1β compared to the AA genotype (<i>p</i> = 0.027) in COPD patients. <i>NLRP8</i> rs306481 minor allele genotypes (AG + AA) were more common in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of group A (<i>p</i> = 0.0083). Polymorphisms in <i>NLRP1</i> (rs12150220; OR = 0.55, <i>p</i> = 0.03) and <i>NLRP4</i> (rs12462372; OR = 0.36, <i>p</i> = 0.03) were only nominally associated with COPD risk. In conclusion, coding polymorphisms in <i>NLRP1</i> rs12150220 show an association with COPD disease severity, indicating that the fine-tuning of the NLRP1 inflammasome could be important in maintaining lung tissue integrity and treating the chronic inflammation of airways.