Il-4 receptor alpha chain q576r rr genotype is associated with increased markers of type 2 inflammation in aspirin exacerbated respiratory disease

In the US, chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by elevated levels of IL-4 and IL-13. Several single nucleotide polymorphisms within the gene encoding for the shared IL-4 receptor alpha chain have been identified, including Q576R (c.1727A>G). The frequency of the RR genotype was significantly higher among asthmatics and the variant was associated with more severe lower airway disease. The impact of the RR genotype in CRSwNP is unclear. Genotyping was performed to determine the frequency of the Q576R polymorphism in 226 patients with CRSwNP and 74 with Aspirin Exacerbated Respiratory Disease (AERD). Gene expression levels of various type 2 inflammatory mediators in NP were evaluated by RT-PCR from 14 patients with CRSwNP and 29 with AERD. There was a significantly higher frequency of the RR genotype in patients with AERD compared to those with CRSwNP (18% vs 6%; p=0.007) and compared to the subset of CRSwNP patients with asthma (18% vs 5%; p=0.01). Compared to AERD patients with the QQ genotype, those with at least one R allele (QR/RR) had significantly higher mean tissue expression levels (% expression of GUSB) of CCL26 (74 vs 29; p=0.03), MUC5AC (3,274 vs 1,801; p=0.04), and POSTN (1,505 vs 562; p=0.04). Similar differences were not observed in patients with CRSwNP based on genotype. The frequency of the RR genotype is elevated in AERD patients and is associated with enhanced expression of type 2 inflammatory mediators. Similar findings were not observed in CRSwNP suggesting a fundamental pathophysiological difference between AERD and CRSwNP.