The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery.

Chronic rhinosinusitis (CRS) affects 14% to 16% of the population.1 This results in both a burden on patient quality of life (QoL) as well as a tremendous socioeconomic impact, with annual direct costs of the disease in excess of $8 billion in the United States alone.2 Over the past 3 decades substantial effort has been invested in better understanding the disease process, with significant progress made in our understanding of mucosal immunology and microbiology.3 Many contributing factors have been implicated in the development of CRS, including allergic responses, impaired mucociliary clearance, immune dysfunction, impaired epithelial defense, microbial colonization/infection, and exposure to environmental pollutants.4,5 It has been conjectured that a genetic component may, in certain environmental situations, lead to the development of CRS. This is based on a number of factors. Individuals with CRS are more likely to report a positive family history than those without CRS.6–8 Additionally, reports of families with unusually high prevalence of both CRS with and without nasal polyps have been published.7–10 Two well-known genetic causes for CRS, cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), have been well characterized (although they account for a small subset of CRS patients). Finally, the inflammatory changes associated with CRS have similarities to those seen in patients with allergic rhinitis and asthma, which are disease processes with well-established genetic components. 11, 12 Although Hsu et al. 13 recently published a comprehensive review of the available literature on genetic studies in CRS, none have been definitively proven to contribute to the disease process. An emerging gene family that may have a genetic contribution to CRS is the bitter taste receptor. Several recent reports have demonstrated the expression of bitter taste receptors in airway epithelium.14–16 We have recently demonstrated that 1 particular bitter taste receptor expressed in the sinonasal ciliated cell, T2R38, is activated by acyl-homoserine lactones (AHLs). AHLs are Gram-negative quorum-sensing molecules used to regulate the expression of genes involved in biofilm formation, persistence, virulence, and other life cycle processes.17–19 When activated by AHLs, in vitro, T2R38 generates a calcium-dependent increase in nitric oxide (NO) production, which subsequently increases mucociliary clearance (MCC) and diffuses into the overlying mucus layer where it also has bactericidal effects.18 Thus, T2R38 contributes to sinonasal mucosal innate immunity by acting as a sentinel for detection of a subset of microbial quorum-sensing molecules and rapidly activating potent local defenses in response to imminent microbial attack. The activity of this sinonasal innate defense response varies depending on 3 common polymorphisms within the TAS2R38 gene. The differences lie in the amino acid residues at positions 49, 262, and 296; these 3 polymorphisms tend to segregate together, yielding 2 common haplotypes. The functional (protective) allele of the receptor encodes a proline, alanine, and valine (PAV) at the respective positions, and a nonfunctional (nonprotective) allele of the receptor encodes an alanine, valine, and isoleucine (AVI) at these positions.20 The 2 common haplotypes generate 3 common genotypes: PAV/PAV, PAV/AVI, and AVI/AVI, which follow classic Mendelian genetics with a 25%, 50%, 25% population distribution, respectively.20 This distribution varies by both geographic region as well as race and ethnicity. Our prior work demonstrated that primary human sinonasal epithelial cultures derived from patients that were PAV/PAV yielded a significant increase in NO production and MCC in response to low levels of AHLs, compared to the cultures derived from PAV/AVI or AVI/AVI patients. We previously reported on a pilot investigation of 28 medically recalcitrant CRS patients who progressed to require functional endoscopic sinus surgery (FESS), which demonstrated a statistically significant skewing from the expected population distribution, with higher than expected nonfunctional genotype (AVI/AVI) individuals and a lower than expected functional (protective) genotype (PAV/PAV) individuals.21 This is a follow-up investigation with a larger series, including those previously reported patients. Our goal was to further confirm the findings of our pilot study and thereby corroborate the relationship between increased risk of failing medical therapy and the AVI/AVI genotype as compared to the protective PAV/PAV genotype. To improve our methodology we also compared our patient population to a regional control population. We also explored whether other known risk factors for CRS, including asthma, allergies, smoking status, polyps, and aspirin sensitivity, segregated with the different TAS2R38 genotypes.