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Genetic Polymorphisms in DNA Repair Gene APE1/Ref-1 and the Risk of Neural Tube Defects in a High-Risk Area of China

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Apurinic/apyrimidinic endonuclease 1/redox-factor 1 (APE1/Ref-1) gene encodes a multifunctional protein involved in the DNA base excision repair (BER) pathway, which initiates repair of apurinic/apyrimidinic (AP) sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone. APE1/Ref-1 polymorphisms are related to the occurrence of neural tube defects (NTDs), but the association between APE1/Ref-1 polymorphisms and NTDs is not reported in Chinese Han population. The aim of the present study was to evaluate the association of APE1/Ref-1 polymorphism and the risk of NTD occurrence for Han population in a high-risk area of China. APE1/Ref-1 genotypes were determined by iPLEX Gold SNP genotyping. AP sites and folate level of brain tissues were measured. The results showed that three polymorphisms (rs3136817, rs77794916, and rs1760944) of APE1/Ref-1 were statistically associated with NTD subtypes. Allele C of rs3136817, allele T of rs77794916, and allele G of rs1760944 were associated with an increased risk for encephalocele (OR = 2.52, 95% CI [1.25–5.07], P < 0.01; OR = 1.80, 95% CI [1.04–3.12], P = 0.04; and OR = 1.96, 95% CI [1.12–3.45], P = 0.02), compared with those harboring the alleles T, C, and T, respectively. The folate level in NTDs was lower than that in controls. DNA AP sites in the encephalocele were significantly higher than the control (P < 0.01). The three polymorphisms of APE1/Ref-1 were significantly related to NTD occurrence, which indicated that APE1/Ref-1 might be a potential genetic risk factor for encephalocele in a high-risk area of NTDs in China.

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Acknowledgements

We thank all obstetricians in the local hospital at Shanxi province, and the pathologists in the department of pathology for the diagnostic work. We also thank all subjects and their family members for their cooperation in providing clinical information and samples for the study. We appreciate the help offered by Prof. Jing Pan and M. Med. Guimin Huang during the process.

Funding

This study was supported by the National Key Basic Research Program (2018YFC10025002, 2018YFC10025003), the Joint Foundation Program of Beijing Municipal Natural Science Foundation and Beijing Municipal Education Commission (KZ201810028045), the National Nature Science Foundation of China (81571443 to JW, 81600984 to XW, 81700777 to ZG), the Beijing Natural Science Foundation (7172038 to JW), and the Research Foundation of Capital Institute of Pediatrics (FX-2018-05).

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Correspondence to Jianhua Wang.

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The study was approved by the Ethics Committee Review Board of Capital Institute of Pediatrics.

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Supplementary Information

Supplementary Figure 1

The association of DNA AP sites or folate level among genetic polymorphisms. A The association between genetic polymorphisms and DNA AP sites in rs3136817 or rs77794916 or rs1760944; B The association between genetic polymorphisms and folate levels in rs3136817 or rs77794916 or rs1760944 (TIF 79002 kb)

Supplementary Table 1

The primers and UEP sequences (DOCX 16 kb)

Supplementary Table 2

Genotype frequency distributions of the SNPs in APE1/Ref-1 genes. Cod: codominant genetic model, Dom: dominant genetic model, Rec: recessive genetic model (DOCX 29 kb)

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Wang, X., Yue, H., Li, S. et al. Genetic Polymorphisms in DNA Repair Gene APE1/Ref-1 and the Risk of Neural Tube Defects in a High-Risk Area of China. Reprod. Sci. 28, 2592–2601 (2021). https://doi.org/10.1007/s43032-021-00537-y

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