Exploring the interaction between FGF genes and T-box genes among Chinese non-syndromic cleft lip with or without cleft palate case-parent trios.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Genetic variants causing syndromic orofacial clefts can also contribute to the etiology of NSCL/P. The purpose of the present study was to explore gene-gene (G×G) interaction using common single nucleotide polymorphic (SNP) markers in fibroblast growth factor (FGF) family and its receptors and T-box genes, which were associated with syndromic orofacial clefts. Our study was conducted in 806 Chinese NSCL/P case-parent trios drawn from an international consortium. A total of 252 SNPs in FGF8, FGF10, FGFR1, FGFR2 and TBX5 passed the quality control criteria and were included in the analysis. The interactions between SNPs in different genes were assessed using Cordell's method, which fitted a conditional logistic regression model. The analysis was performed using the R-package trio (Version 3.8.0). Bonferroni correction was used to adjust for multiple comparisons, and the overall significance threshold was set as P= 1.98×10-4 (0.05/252). Conditional logistic regression revealed the most significant interaction between rs2330542 in FGF10 and rs1946295 in TBX5, which remained significant (P=9.63×10-6 ) after Bonferroni correction. The relative risk of allele C in rs2330542 (FGF10) was 1.02 (95%CI 0.81-1.28), while the relative risk was 1.42 (95%CI 1.03-1.97) when the exposure was a combination of allele C in rs2330542 and allele A in rs1946295 (TBX5). Our findings confirmed the importance of considering G×G interaction when exploring the genetic risk factors of NSCL/P. Further investigations are warranted to validate the potential interaction and reveal the biological function of FGF10/FGFR2/TBX5. This article is protected by copyright. All rights reserved.