A functional indel polymorphism rs34396413 in TFAP2A intron-5 significantly increases female encephalocele risk in Han Chinese population

Purpose Transcription factor AP-2 alpha (TFAP2A) is an important transcriptional factor involved in various aspects of embryo development including neural tube closure. Tfap2a deficiency led to the failure of cranial neural-tube closure in mice and other model organisms. However, it remains largely unknown about the relationship between TFAP2A variants and human cranial neural tube defects (NTDs). The aim of this study was to find the association between TFAP2A intronic SNP rs3439413 and NTDs and to explore its function. Methods We found an indel polymorphism rs3439413 in TFAP2A intron-5 from our previous target sequencing project. In this study, we validate its association with human NTDs in Shanxi group containing 266 NTD cases and 295 matched controls. Then, we investigated its function on transcriptional activity by dual-luciferase assays and EMSA. Results The minor allele of rs34396413 significantly increased the risk of NTD in a Han Chinese population of Shanxi Province ( P = 0.0082, OR = 1.45, 95%CI = 1.10–1.90), especially the risk of encephalocele for female ( P = 0.0064, OR = 2.46, 95%CI = 1.22–4.94). Functional analysis revealed the minor allele of rs34396413 decreases transcriptional activity and attenuates transcription factor binding affinity. Conclusion We have demonstrated that the minor allele of rs34396413 was a risk factor of NTD in the Shanxi group, providing new insight into the study of NTD etiology.