Cystic fibrosis transmembrane conductance regulator function, not TAS2R38 gene haplotypes, predict sinus surgery in children and young adults with cystic fibrosis

Abstract

Background Chronic rhinosinusitis symptomatology begins in early childhood individuals with cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to sinus development and disease. Genetic variants of the bitter taste receptor TAS2R38 have been suggested to contribute to sinus disease severity in individuals without CF. Our objective was to explore whether functional TAS2R38 haplotypes and CFTR function are associated with sinus disease or the need for sinus surgery in individuals with CF. Methods We conducted a retrospective study using prospectively collected data from the CF Twin‐Sibling Study. The function of CFTR was assessed via chloride conductance. Genotyping of the TAS2R38 gene identified patients who were homozygous for the functional haplotype, heterozygous, or homozygous for nonfunctional haplotypes. Clustered multivariate logistic regression was performed, controlling for sex and family relationship. Results A total of 1291 patients were evaluated. Patients with ≤1% CFTR function were 1.56 times more likely to require sinus surgery than those with >1% CFTR function (p = 0.049). CFTR function did not correlate significantly with the presence of sinus disease (p = 0.30). In addition, there were no statistically significant differences in diagnosis of sinus disease or need for sinus surgery between patients with functional and nonfunctional TAS2R38 haplotypes. Conclusion CFTR function correlates with need for sinus surgery, whereas TAS2R38 function does not appear to contribute to sinus disease or the need for sinus surgery in patients with CF.

Taste receptors in chronic rhinosinusitus, what is the evidence? A systematic review

“…In an Italian population of patients with CFTR mutations and concurrent CRS, the PAV allele was associated with a decreased need for ESS 30 . The third study reported no correlation between the TAS2R38 diplotype and incidence of CRS or need for ESS 31 …”

“…Finally, there is a lack of institutional and geographic diversity in the included studies. Fourteen studies were done in the United States (Philadelphia [9], 12,16,18,24,26,27,29,37,39 South Carolina [1], 25 West Virginia [1], 20 Colorado [2], 38,40 and unspecified [1] 31 ), 5 in Italy, 17,19,28,30,32 1 in Canada, 21 1 in Poland, and 1 in Australia 23 . Despite the leading role of the University of Pennsylvania in pioneering this field and conducting 9 of 14 of the included US studies, increased genetic and geographic diversity of patients will be important given inherent differences in the distribution genetic of TR genes.…”

“…The study populations were primarily white, with all 12 studies reporting >75% to 85% white patients. 12,16,18,19,21,[24][25][26][27]29,31,37 A more diverse patient population is needed to understand whether the role of extraoral TRs in CRS is consistent among patients of different racial backgrounds. In addition, methodologic differences in phenotype and genotype studies introduce limitations that make it difficult to fully assess the aggregate effect of bitter TRs on CRS.…”

HSP90 modulates T2R bitter taste receptor nitric oxide production and innate immune responses in human airway epithelial cells and macrophages

“…The importance of T2Rs in upper airway defense is supported by observations that patients homozygous for the AVI TAS2R38 polymorphism, which renders the T2R38 receptor non-functional, have increased frequency of gram-negative bacterial infection (18), have higher levels of sinonasal bacteria in general (45,46) and specifically have higher levels of biofilmforming bacteria (47), have higher frequency of chronic rhinosinusitis (48)(49)(50)(51), and exhibit worse outcomes after functional endoscopic sinus surgery (52). One study has suggested that TAS2R38 genetics may also play a role in cystic fibrosis P. aeruginosa infection (53), though other studies have suggested that TAS2R38 may not be a modifier gene in CF (54,55).…”

Epidemiology of Chronic Rhinosinusitis: Prevalence and Risk Factors

“…This has been further validated in linkage studies, 72 and mutations appear to be predictive of medically recalcitrant CRS and the need for surgical intervention. 73,74 Another noted genetic target is the bitter taste receptor T2R38, encoded by the TAS2R38 gene, which plays a role in sinonasal epithelial defense against gram-negative organisms (eg, Pseudomonas aeruginosa) and mucociliary clearance. 75,76 This gene is prone to polymorphisms that may affect innate host defense mechanisms and increase susceptibility to biofilm formation.…”