Genetic Associations with Non-Syndromic Cleft Lip/Palate and Dental Caries in Kuwaiti Patients: A Case-Control Study

Background: Non-syndromic cleft lip/palate (NCL/P) is a prevalent congenital anomaly. Despite an unclear epidemiological link between orofacial clefts and dental caries, genetic studies suggest that polymorphisms in taste receptor genes may influence caries risk. Objectives: This study had two primary objectives: (1) to compare SNPs in NCL/P-associated genes (IRF6, FOXE1) between Kuwaiti NCL/P cases and controls, and (2) to explore whether variants in caries-associated (KLK4, DSPP) and taste receptor (TAS1R2, TAS2R38) genes are associated with dental caries susceptibility in individuals with NCL/P, independent of overall caries prevalence. Methods: A case-control design was employed, with 25 NCL/P cases and 25 unaffected controls recruited from a Dental Craniofacial Clinic in Kuwait. Genomic DNA was extracted from buccal swabs, and SNP genotyping was performed using real-time PCR for genes related to NCL/P, dental caries, and taste perception. Caries status was assessed using the dmft/DMFT scoring system. The genotyped genes included NCL/P-related (IRF6, FOXE1), caries-related (KLK4, DSPP), and taste receptor genes (TAS1R2, TAS2R38). Results: At nominal significance, KLK4, DSPP, and TAS1R2 showed associations with NCL/P status, while IRF6 and FOXE1 did not. After applying Benjamini-Hochberg FDR correction across 10 SNPs, no allele- or genotype-level association remained significant (q < 0.05). The strongest signal was KLK4 rs2235091 (allele-level p = 0.016; q = 0.159). An exploratory age- and sex-adjusted logistic model for KLK4 suggested a possible effect (aOR 0.40; 95% CI 0.18-0.87; p = 0.021). Within-group analyses of caries burden revealed no associations that survived FDR control (lowest q = 0.056 for FOXE1 in controls). Conclusions: After controlling for multiple testing, no SNP showed a statistically significant association with NCL/P or caries burden. Nominal signals for KLK4, DSPP, and TAS1R2 did not survive FDR correction; an exploratory adjusted model suggested a possible KLK4 effect, but this requires cautious interpretation. The small sample size is a key limitation, and the findings highlight the need for larger, well-powered studies to clarify genetic contributions to NCL/P and caries risk.