Rs61731397-C in OR2A25 increases the risk of chronic rhinosinusitis in the Chinese population

Chronic rhinosinusitis (CRS) is a multifactorial disorder driven by intricate interactions between genetic predispositions and environmental factors. Despite extensive research, the genetic underpinnings of CRS remain largely elusive.

Our aim was to identify genetic risk variants associated with CRS in the Chinese population and elucidate the underlying mechanisms.

We performed a discovery genome-wide association study of CRS using a population-based Kunshan cohort and validated the results in an independent clinical-based Beijing cohort. Functional characterization of the identified variant, rs61731397 in the olfactory receptor gene OR2A25, was conducted by using structural prediction, in vitro expression studies in human cell lines, and Western blot analysis. To explore the potential role of OR2A25, we reanalyzed published single-cell RNA sequencing data from analysis of nasal tissue (HRA000772).

A genome-wide significant association was found between rs61731397 and increased risk of CRS in both the discovery (odds ratio = 1.39, P = 3.30 × 10^-8) and replication (odds ratio = 1.53, P = 4.6 × 10^-3) cohorts. In vitro analyses demonstrated that the rs61731397-C allele decreased OR2A25 protein stability, leading to reduced expression levels. Single-cell RNA sequencing data analysis indicated that OR2A25 was predominantly expressed in T cells and epithelial cells in the nasal mucosa. Consistent with this, a reduction in OR2A25 expression was observed in T cells as well as epithelial cells from patients with CRS versus that in healthy controls.

Our findings demonstrate that the missense variant rs61731397-C in OR2A25 increases the risk of chronic rhinosinusitis in the Chinese population. This variant may contribute to CRS pathogenesis by downregulating OR2A25 expression, potentially affecting immune responses in the nasal mucosa.