[Parent-of-origin effects of FGF/FGFR signaling pathway candidate gene polymorphisms on the risk of non-syndromic cleft lip with or without cleft palate].

Objective: To investigate the parent-of-origin effects (POE), interactions between imprinted and non-imprinted genes, and POE-environment interactions of candidate genes in the FGF/FGFR signaling pathway on the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Methods: A case-parent trio design was adopted, including 806 NSCL/P trios (2 418 individuals). Single-locus POE was estimated using log-linear models; interactions between imprinted and non-imprinted genes were analyzed using the Cordell method; and POE-environment interactions were assessed via the Wald test. Bonferroni correction was applied for multiple testing. A total of 379 single-nucleotide polymorphisms (SNPs) located on two imprinted genes (FGF12 and FGF14) and 17 non-imprinted genes within the FGF/FGFR signaling pathway were included in the NSCL/P trio analysis. Results: Single-locus POE analysis identified 23 SNPs in FGF12, FGF14, FGFR2, FGF1, and FGFR1 with potential POE (all P<0.05). However, none remained statistically significant after Bonferroni correction (all P>1.32×10-⁴). Interaction analysis of the 23 SNPs with potential POE revealed positive signals between 9 SNP pairs from the imprinted gene FGF14 and the non-imprinted gene FGFR2, and 1 SNP pair from FGF14 and FGF1 (all P<0.05). The interaction between FGF14 rs9518631 and FGFR2 rs10510097 remained statistically significant after Bonferroni correction (P=1.97×10-³). POE-environment interaction analysis indicated that the POE of 5 SNPs located on FGF14, FGFR2, and FGFR1 were influenced by maternal passive smoking during pregnancy, and the POE of FGFR2 rs10510097 was influenced by maternal multivitamin supplementation during pregnancy (all P<0.05). However, none of these findings remained statistically significant after Bonferroni correction (all P>2.17×10-³). Conclusion: The FGF/FGFR signaling pathway may influence the risk of NSCL/P through interactions between the imprinted gene FGF14 and the non-imprinted gene FGFR2.