CD8A gene polymorphisms predict severity factors in chronic rhinosinusitis

Abstract

A genetic basis to chronic rhinosinusitis (CRS) is postulated, but remains elusive. We have recently identified low levels of circulating CD8 lymphocytes as a frequent finding in difficult-to-treat or refractory CRS. In major histocompatibility complex 1 class 1 (MHC1) deficiency, low circulating levels of CD8 lymphocytes secondary to mutations in the cluster of differentiation 8a (CD8A), tapasin 1 (TAP1), tapasin 2 (TAP2), or tapasin binding-protein (TAPBP) genes lead to a clinical syndrome, which is associated with severe CRS. The objective of this work was to identify whether genetic factors associated with MHC1 deficiency are present in CRS. Previous results from a genomewide association study of CRS were screened for polymorphisms in the CD8A, TAP1, TAP2, and TAPBP genes associated with MHC1 immunodeficiency syndrome. Significant polymorphisms were tested for associations with demographic factors characterizing severe CRS. Polymorphisms in the CD8A (rs3810831) and TAPBP (rs2282851) genes were significantly associated with CRS. Major allele homozygosity for CD8A (rs3810831) was associated with a higher frequency of affected relatives (p = 0.052), increased severity as characterized by age at diagnosis (p = 0.009), age at first surgery (p = 0.004), and number of surgeries (p = 0.008), whereas TAPBP (rs2282851) was associated increased risk for CRS (odds ratio [OR] = 2.48, p = 0.0076). Modified CD8A or TAPBP gene function may contribute to the development of refractory CRS via altered MHC1 function and reduction of circulating CD8 lymphocytes. Identification of markers in the CD8A or TAPBP genes via sequencing may offer a basis for genetic testing in CRS.