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目的 非综合征型唇裂合并或不合并腭裂(NSCL/P)是一类常见的出生缺陷,遗传致病因素一直是其病因学研究的热点.本研究拟基于家系设计在WNT代谢通路基因中探索亲源效应对NSCL/P发病风险的影响.方法 本研究人群为“唇腭裂的基因组学国际合作组研究”项目在中国地区募集的806个NSCL/P核心家系.利用对数线性模型探索WNT基因及其单体型的亲源效应与疾病的关联,采用Wald检验探索亲源效应与环境因素的交互作用.经过Bonferroni多重检验校正后,统计学检验的显著性阈值设为P＜3.47×10-4.结果 质量控制后共纳入7个基因上144个单核苷酸多态性位点进行分析.结果 显示,NSCL/P家系中有8个位点具有潜在的亲源效应(P＜0.05),但经Bonfcrroni多重检验校正后,均未达到统计学显著性水平(P＞3.47×10-4).NSCL/P家系中位于WNT9A rs4074668-rs 12725747单体型(T-A)具有亲源效应,且经Bonferroni校正后差异仍有统计学意义(P=2.74×10-4).但该单体型的亲源效应与环境因素(被动吸烟、复合维生素补充)的交互作用并未达到统计学显著水平.结论 WNT代谢通路基因可能通过亲源效应影响NSCL/P的发生风险.位于WNT9A基因rs4074668-rs 12725747单体型(T-A)亲源效应与NSCL/P发病风险存在显著关联.未来仍需其他独立样本验证以进一步确认WNT代谢通路在NSCL/P发生中的作用.

Objective Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with its genetic evidence widely explored.This study explored the potential the parent-of-origin (PoO) effect of WNT pathway on the risks of NSCL/P,using a case-parent trio design.Methods Data on the single nucleotide polymorphism (SNP) of WNT genes were selected from a genome-wide association study (GWAS).A total of 806 Chinese non-syndromic cleft lip patients,with or without cleft palate (NSCL/P) case-parent trios,were gathered from an international consortium.PoO effect of WNT pathway genes and its haplotypes were explored by log-linear models.Additional Wald tests were performed to assess:a) the heterogeneity of PoO effect between different maternal exposures,b) the interaction between PoO effect,c) maternal exposure to environmental tobacco smoke (ETS),and d) multivitamin supplementation during pregnancy.The threshold for statistical significance was adjusted as 3.47 × 10-4,according to Bonferroni correction.Results After quality control,a total of 144 SNPs within seven genes were included for analyses,among which 8 SNPs were of potential PoO effect (P＜0.05).However,none of them achieved the statistical significance after Bonferroni correction.The haplotype rs4074668-rs12725747 (T-A) on WNT9A showed significant PoO effect,based on the haplotype test for PoO (P=2.74 × 10-4).In addition,no statistically significant interaction was found in further exploration of this haplotype under environmental exposures as ETS or multivitamin supplementation.Conclusions Genes in the WNT pathway may influence the NSCL/P risks through the potential PoO effect.Particularly,the haplotype rs4074668-rs12725747 (T-A) on WNT9A presented significant PoO effect on NSCL/P,statistically.From this current study,findings on WNT pathway related risks among the NSCL/P,need to be further validated by independent samples in the future.