Further insights into the role of the annexin A5 M2 haplotype as recurrent pregnancy loss factor, assessing timing of miscarriage and partner risk

Tüttelmann, Frank; Ivanov, P; C, Dietzel; Sofroniou, Anna; Tsvyatkovska, Tsvetomira M.; Komsa-Penkova, Regina; Markoff, Arseni; Wieacker, P.; Bogdanova, Nadja

doi:10.1016/j.fertnstert.2013.06.046

Cited by 34 publications

(79 citation statements)

References 25 publications

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“…The odds ratios of M2-carrying RPL patients from this study, 1.4 with population controls and 1.9 with parous women, are similar to these of European RPL cohorts, 1.5 to 2.5 with population controls and 3 to 5 with parous controls [5,21,22], as well as to the reported odds ratio of 2.4 with parous women from the Japanese study [20]. Attributable predisposition of male M2 carriers in Malay RPL couples is thus in general agreement with these previous studies, supporting the proposed pathophysiological expression of M2/ANXA5 in impediment of embryonic anticoagulation.…”

Section: Discussionsupporting

confidence: 80%

“…As reported in previous studies, M2 prevalence in population and healthy subject controls of German, Italian, Bulgarian, and UK white European origin are about 15-17% [4,5,14]; whereas in Asian populations, the reported carrier rate is 11% with 5.4% M2 allelic frequency for the Japanese [20]. A recent study finding no association of M2/ ANXA5 with RPL in 86 Estonian and 227 Danish subjects reported 27.3% prevalence with 15.2% allelic frequency in Estonian and 23.5% prevalence with 12.6% allelic frequency in Danish parous women [30].…”

Section: Discussionsupporting

confidence: 69%

“…The estimated odds ratios in M2 carriers were somewhat elevated, 1.8 to 3.0, when compared to healthy controls with at least one live birth and with negative history of pregnancy losses in German [5,14], Italian [4], Bulgarian [5], and Japanese [20] cohorts. However, the criteria for RPL subjects varied slightly between the studies such as the definition of RPL and categories of embryonic development.…”

Section: Introductionmentioning

confidence: 82%

“…RPL is a complex and multifactorial obstetric problem with polygenic background and it involves a variety of genetic, physiological, and environment factors [2]. About 30-40% of RPL cases remain unexplained, categorized as Bidiopathic.Î n the last decade, evidence has linked hereditary thrombophilia to the etiology of RPL by a mechanism of impeded placental perfusion, ultimately resulting in adverse pregnancy outcome [3][4][5][6][7]. Although factor V Leiden (FVL) and prothrombin G20210A (PTm) variants are accounted for 70% of inherited thrombophilia patients [7], both of these factors are rare in Asian population [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…However, the criteria for RPL subjects varied slightly between the studies such as the definition of RPL and categories of embryonic development. In addition to available evidence supporting reduced expression of ANXA5 in chorionic placenta of RPL women, who were M2/ANXA5 carriers [18,19], the male M2/ANXA5 carriers in RPL couples also showed a rather similar risk that would corroborate impeded embryonic anticoagulant function [5,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

Ang

Kathirgamanathan

Ch’ng

et al. 2017

J Assist Reprod Genet

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Purpose The aim of this study was to evaluate a new predisposition factor, M2/ANXA5 (RPRGL3), in recurrent pregnancy loss (RPL) patients of Malay origin, since it was previously known that the prevalence of this condition is relatively high among the Malay population of Malaysia, where conventional hereditary thrombophilia factors have been generally ruled out. Methods A total of 232 women who had experienced ≥2 unexplained RPL and 141 available male partners were recruited, with 360 healthy Malay and 166 parous female controls. Prevalence of M2 carriage and RPL odds ratios were calculated in (a) control and patient groups; (b) clinically defined subgroups in categories of pregnancy loss, primary, secondary, and tertiary; and (c) timing of pregnancy loss in early, ≤15th gestation week and Blate^fetal losses, and >15th gestation week subgroups.Results Both male and female subjects had similar M2/ ANXA5 allele frequencies. The carrier rate of M2/ANXA5 for the general Malay population was 42.2 and 34.9% for parous controls. These carrier rates compared to Malay RPL subjects (52% M2 carriers) resulted in elevated odds ratios (95% confidence interval) of 1.53 (1.1 to 2.1) and 1.97 (1.3 to 3.1) accordingly for early fetal losses. Moreover, exceeding copy numbers of M2/ANXA5 alleles seemed to afflict a greater chance of RPL in couples, especially when both partners were M2 carriers. Conclusion This study confirmed the proposed role of M2/ ANXA5 as embryonic, genetically associated thrombophilia predisposition factor for early RPL among ethnic Malay of Malaysia.Keywords Annexin A5 . M2/ANXA5 . Recurrent pregnancy loss (RPL) . MiscarriageElectronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

Ang

Kathirgamanathan

Ch’ng

et al. 2017

J Assist Reprod Genet

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

Luo

Wang

Zhang

et al. 2019

Journal Cellular Physiology

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The expression of annexin A5 (ANXA5) was shown to affect the pathogenesis of recurrent pregnancy loss (RPL). In this study, the effects of two haplotypes, M1 and M2, on the transcription efficiency of ANXA5 promoter were explored. Correlation analysis was used to investigate the association between the single‐nucleotide polymorphism haplotypes in ANXA5 promoter and the risk of RPL. And a luciferase reporter assay was carried out to study the effects of haplotypes M1 and M2 on the transcription efficiency of the ANXA5 promoter. To study the association between ANXA5 haplotypes and the risk of RPL, real‐time polymerase chain reaction, western blot analysis, and immunohistochemistry assays were conducted to observe the expressions of ANXA5 messenger RNA (mRNA) and protein. Compared to M1 haplotype carriers, M2 haplotype carriers were associated with a higher risk of RPL. Additionally, compared to GATGTC haplotype carriers, GATGGC haplotype carriers were associated with a higher risk of RPL. Compared with RPL cases, the incidences of M2 haplotype were lower in both the population control and parous control cases. Furthermore, M2 carriers showed more significantly decreased activity of ANXA5 promoter compared to the carriers of other haplotypes, indicating that the haplotypes of ANXA5 promoter may be used as a potential biomarker to predict the prognosis of RPL. Moreover, the activity of ANXA5 as well as the mRNA/protein expression of ANXA5 was significantly downregulated in RPL patients, indicating that the M2 haplotype significantly increased the risk of RPL. Therefore, haplotype M2 increased the risk of RPL by inhibiting the expression of ANXA5.

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Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications

Rogenhofer

Nienaber

Amshoff³

et al. 2017

J Assist Reprod Genet

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Further insights into the role of the annexin A5 M2 haplotype as recurrent pregnancy loss factor, assessing timing of miscarriage and partner risk

Cited by 34 publications

References 25 publications

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population

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

Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications

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