Exploring the role of SNPs in genes related to sweet taste perception and intake (SweetG) in Primary Ciliary Dyskinesia (PCD) and its clinical manifestations.

Introduction: PCD is a rare congenital ciliopathy characterized by defective mucociliary clearance in the respiratory epithelium, leading to recurrent infections of the upper and lower airways. Recent studies revealed that SweetG can modulate immune response, ciliary beat frequency, and mucus secretion, suggesting a link between taste signaling and mucosal defense mechanisms; this opens new perspectives on the complex pathophysiology of PCD. Aim: To investigate whether 1) SNPs in SweetG occur at different frequencies in PCD patients compared to the general population, and 2) they are associated with specific clinical features of the disease. Methods: A total of 34 PCD patients (10–69 yrs, 56% females) were genotyped via SNP arrays, followed by imputation with TOPMed. Allele frequencies of 26 SNPs in 15 SweetG were compared between PCD cohort with reference populations data (1000G EUR, gnomAD v4.1.0 NFE) using a binomial test. Logistic and linear regressions assessed SNP-SweetG associations with PCD clinical features. Results: 1) A statistically significant higher frequency between PCD patients and reference populations was observed for four SNPs within three SweetG: • rs838133 and rs838145 (FGF21), • rs58931966 (RGS9), • rs2654185 and rs5415 (SLC2A4). 2) rs838133 and rs838145 (FGF21) were associated with the situs inversus presence (OR = 11.13, OR = 4.69). Notably, FGF21 belongs to the FGF family, that is known to play a key role in embryogenesis, and determination of the left-right axis. Further, rs838133 was also associated with lower BMI (beta = -1.42), in line with data describing FGF21’s role in metabolic disorders. In addition, we found that rs5415 within the SLC2A4 gene, encoding the glucose transporter GLUT4, was associated with a lower risk of chronic rhinosinusitis (OR = 0.005). Given SLC2A4’s role in glucose uptake and inflammatory pathways regulation, this finding suggests a potential link between glucose metabolism and sinonasal inflammation. Conclusions: This study uncovers novel associations between SweetG and clinical features of PCD. These findings suggest that variants in SweetG may be involved in modulating phenotypic variability, thus contributing to a deeper understanding of the genetic architecture underlying PCD.