Genetic variations and haplotypes in the annexin A5 gene are associated with the risk of recurrent pregnancy loss

Luo, Yanli; Wang, Jing; Zhang, Qinghua; Yang, Xuezhou; Li, Lin; Yin, Jiu; Li, Hemei; Xuan, Shi‐Ying; Chen, Zhilan; Liu, Yun

doi:10.1002/jcp.28463

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…Studies have suggested that ANXA5 is related to RSA (22)(23)(24)(25). Lan et al found that reduced ANXA5 expression was associated with a higher risk of RSA (26). Furthermore, the haplotype in the proximal core promoter region of ANXA5 gene, including rs28717001, rs112782763, rs113588187, and rs28651243, is associated with URSA (23).…”

Section: Discussionmentioning

confidence: 99%

Identification of genetic polymorphisms in unexplained recurrent spontaneous abortion based on whole exome sequencing

Mou

Huang

et al. 2022

Ann Transl Med

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Background: The precise etiology of approximately 50% of patients with recurrent spontaneous abortion (RSA) is unclear, known as unexplained recurrent spontaneous abortion (URSA). This study identified the genetic polymorphisms in patients with URSA.Methods: Genomic DNA was extracted from 30 couples with URSA and 9 couples with normal reproductive history for whole exome sequencing. Variations in annotation, filtering, and prediction of harmfulness and pathogenicity were examined. Furthermore, predictions of the effects of changes in protein structure, Sanger validation, and functional enrichment analyses were performed. The missense mutated genes with significant changes in protein function, and genes with mutations of premature stop, splice site, frameshift, and in-frame indel were selected as candidate mutated genes related to URSA.Results: In 30 unrelated couples with URSA, 50%, 20%, and 30% had 2, 3, and more than 4 miscarriages, respectively. Totally, 971 maternal and 954 paternal mutations were found to be pathogenic or possibly pathogenic after preliminary filtering. Total variations were not associated with age nor the number of miscarriages. In 28 patients (involving 23 couples), 22 pathogenic or possibly pathogenic variants of 19 genes were found to be strongly associated with URSA, with an abnormality rate of 76.67%. Among these, 12 missense variants showed obvious changes in protein functions, including ANXA5 (c.949G>C; p.G317R),

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Section: Discussionmentioning

confidence: 99%

Identification of genetic polymorphisms in unexplained recurrent spontaneous abortion based on whole exome sequencing

Mou

Huang

et al. 2022

Ann Transl Med

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“…In addition, there is a close relationship between the M2 haplotype and the occurrence of pre-eclampsia and gestational disorders, while the susceptibility to FGR is increased by M2 haplotype (29,30). It has also been shown that the activity of ANXA5 promoter in placental tissue samples harvested from patients with RPL was markedly reduced to decrease Anxa5 expression, suggesting that the M2 haplotype increased RPL risk by reducing the expression of Anxa5 (31). In the present study, the luciferase assays demonstrated that the M2 haplotype was responsible for the transcription efficiency of the ANXA5 promoter.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of ANXA5 haplotype and its effect on recurrent pregnancy loss

et al. 2021

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Recurrent pregnancy loss (RPL) is often associated with dysregulated Annexin A5 (ANXA5) expression. Moreover, the variants of Anxa5, a protein that is enriched in the placenta to prevent coagulation, have been reported to affect RPL risks. The haplotypes M1 [including single nucleotide polymorphisms (SNPs) 1A/C and 27T/C] and M2 (including SNPs 19G/A, 1A/C, 27T/C and 76G/A) of ANXA5 were also reported to affect RPL risks. The present study aimed to investigate the association between the haplotype located in the promoter region of ANXA5 and the risk of RPL. Patients with RPL (n=235) or intrauterine fetus death (IUFD; n=154), as well as healthy control subjects (n=375) were enrolled in the current research. Their haplotypes of ANXA5 were determined using genotyping, and the association between ANXA5 haplotypes and the risk of RPL was accordingly analyzed. A luciferase assay was conducted to investigate the haplotype responsible for ANXA5 activity. Reverse transcription-quantitative PCR, western blot analysis, immunohistochemistry and ELISA were performed to assess the expression level and activity of ANXA5 in patients with RPL. Consequently, the majority (n=214) of patients with RPL had a history of early RPL, whereas 31 patients with RPL had a history of both early and late RPL episodes. A significant difference was found between cases and controls in terms of gravidity and parity, whereas no significant differences were found in terms of age. The percentage of patients with RPL carrying the M2 haplotype of ANXA5 was significantly higher compared with that in control subjects, indicating that the M2 haplotype of ANXA5 was an independent risk of RPL as it influenced the transcription efficiency of ANXA5 promoter. In patients with RPL, ANXA5 activity was suppressed and the mRNA and protein expression levels of Anxa5 were decreased. Thus, the ANXA5 M2 haplotype may be an independent risk factor of RPL by affecting Anxa5 activity.

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