目的: 探索亚裔人群中转化生长因子β(transforming growth factor-β，TGF-β)信号通路基因多态性与非综合征型唇裂合并或不合并腭裂(non-syndromic cleft lip with or without cleft palate，NSCL/P)的关联及可能存在的基因-基因、基因-环境交互作用。方法: 选取1 038个NSCL/P核心家系作为研究对象。对TGF-β信号通路上的10个基因的343个单核苷酸多态性(single nucleotide polymorphism，SNP)位点进行了传递不平衡检验(transmission disequilibrium test，TDT)，采用条件Logistic回归模型进行基因-基因交互作用分析和基因-环境交互作用分析。研究收集的环境因素包括患儿母亲孕期吸烟、被动吸烟、乙醇摄入量以及维生素使用情况。由于患儿母亲孕期吸烟和饮酒暴露率较低(<3%)，因此，仅对母亲孕期被动吸烟及补充多种维生素这两个环境因素与基因之间的交互作用进行了分析。采用Bonferroni法对结果进行多重检验校正，显著性的阈值设置为P=1.46×10^-4。结果: 共有4个基因的23个SNP位点与NSCL/P之间存在关联(P<0.05)，但经过Bonferroni多重检验校正后，这些关联均未达到统计学显著性水平。经过Bonferroni多重检验校正之后，6对SNP[rs4939874(SMAD2)与rs1864615(TGFBR2)，rs2796813(TGFB2)与rs2132298(TGFBR2)，rs4147358(SMAD3)与rs1346907(TGFBR2)，rs4939874(SMAD2)与rs1019855(TGFBR2)，rs4939874(SMAD2)与rs12490466(TGFBR2)，以及rs2009112(TGFB2)与rs4075748(TGFBR2)]存在显著的统计学交互作用(P<1.46×10^-4)，基因-环境交互作用的分析没有达到多重检验校正阈值的显著结果。结论: 未发现TGF-β通路基因多态性与NSCL/P的关联，该通路上部分基因可能通过基因-基因交互作用影响NSCL/P的发病风险。未来仍需其他独立研究的证据支持，以进一步的探索其中潜在的生物学机制。

Objective: To explore the association between polymorphisms of transforming growth factor-β (TGF-β) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction. Methods: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-β signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10^-4, applying Bonferroni correction to account for multiple testing. Results: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P (P<0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 (SMAD2) and rs1864615 (TGFBR2), rs2796813 (TGFB2) and rs2132298 (TGFBR2), rs4147358 (SMAD3) and rs1346907 (TGFBR2), rs4939874 (SMAD2) and rs1019855 (TGFBR2), rs4939874 (SMAD2) and rs12490466 (TGFBR2), rs2009112 (TGFB2) and rs4075748 (TGFBR2) showed statistically significant SNP-SNP interaction (P<1.46×10^-4). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing. Conclusion: The comprehensive evaluation of SNP associations and interactions within the TGF-β signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-β signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.