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

Rogenhofer, Nina; Nienaber, Lara R. M.; Amshoff, Lea C.; Bogdanova, Nadia; Petroff, David; Wieacker, P.; Thaler, Christian J.; Markoff, Arseni

doi:10.1007/s10815-017-1041-0

Cited by 7 publications

(4 citation statements)

References 37 publications

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“…1B) was performed to capture any current related publications. Out of an additional 77 records retrieved, two studies were fully reviewed (30,31). One was excluded due to improper outcome (30), and the other study (31) was included.…”

Section: Characterization Of Studiesmentioning

confidence: 99%

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Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

Ang

Bogdanova²,

Markoff³

et al. 2019

Fertility and Sterility

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Objective: To ascertain the magnitude and precision of the association between M2/ANXA5 haplotype and repeated pregnancy loss (RPL). Design: Meta-analysis of odds ratios. Setting: Not applicable. Patient(s): Subjects were women with RPL and their partners. Intervention(s): Not applicable. Main Outcome Measure(s): The association between M2/ANXA5 haplotype and RPL was evaluated in a meta-analysis of odds ratios. We further scrutinized this association according to [1] the sequence of miscarriages, [2] the number of consecutive losses, [3] the extent of excluding other pathologies of RPL, and [4] the timing of fetal loss. Result(s): Fourteen individual studies (n ¼ 4,664 subjects) were included in this meta-analysis. The results show that women with the M2/ANXA5 haplotype have 1.54 times (95% confidence interval, 1.08-2.20) the odds of having associated RPL compared with women with the normal haplotype, regardless of consecutive or nonconsecutive pregnancy losses. Acknowledging the clinical heterogeneity among the studies, this significant association comes with a caveat that the lower bound of the confidence interval is close to unity. In couple populations (n ¼ 2,449), M2/ANXA5 haplotype subjects have an odds ratio of 1.48 (95% confidence interval, 1.14-1.91) of experiencing RPL, which suggests contributions from paternal M2/ANXA5 carriers in RPL. Conclusion(s):This meta-analysis ascertains that women with the M2/ANXA5 haplotype have a higher risk of experiencing RPL, especially consecutive early idiopathic RPL. Male partners with the M2/ANXA5 haplotype partly contribute to this risk. Hence, screening for the M2/ANXA5 haplotype as a panel of laboratory investigations for RPL is recommended. (Fertil Steril Ò 2019;111: 971-81. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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Section: Characterization Of Studiesmentioning

confidence: 99%

“…Out of an additional 77 records retrieved, two studies were fully reviewed (30,31). One was excluded due to improper outcome (30), and the other study (31) was included. In total, 14 studies (Table 1), which were rated as moderate or strong on the Newcastle-Ottawa scale, were included in the meta-analysis.…”

Section: Characterization Of Studiesmentioning

confidence: 99%

Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

Ang

Bogdanova²,

Markoff³

et al. 2019

Fertility and Sterility

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“…These included annexin A5 (ANXA5) an anticoagulant protein, inhibin beta A chain (INHBA), which is a subunit of both inhibin and activin, transthyretin (TTHY) a thyroid hormone-binding protein, insulin-degrading enzyme (IDE), which binds to insulin and leukaemia inhibitory factor receptor (LIFR). Whilst proteins like ANXA5, inhibins/activins, TTHY and LIFR have been previously reported to be secreted from the placenta 15,45–47 , we are not aware of any studies describing the secretion of other proteins, like IDE from the human placenta. Furthermore, other secreted proteins such as adipocyte enhancer-binding protein 1 (AEBP1) and Y-box-binding protein 1 (YBOX1), which can regulate transcription were also detected in the placental secretome.…”

Section: Discussionmentioning

confidence: 98%

Unbiased placental secretome characterization identifies candidates for pregnancy complications

Napso

Zhao

Lligoña

et al. 2020

Preprint

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Pregnancy requires adaptation of maternal physiology to enable normal fetal development. These adaptations are driven, in part, by the production of placental hormones. Failures in maternal adaptation and placental function lead to pregnancy complications including abnormal birthweight and gestational diabetes. However, we lack information on the full identity of hormones secreted by the placenta that mediate changes in maternal physiology. This study used an unbiased approach to characterise the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones that are important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed using mass spectrometry on cultured primary trophoblast and fluorescence-activated sorted endocrine cells from pregnant mouse dams, and a placenta secretome map containing 319 proteins was generated. Gene ontology analyses showed that a high proportion of placental secretome proteins are involved in metabolic and immune modulation, signalling and growth. The majority of proteins identified are also expressed by human placenta and several have been reported to be dysregulated in pregnancy complications. Moreover, in proof of concept studies, we found that the relative abundance of secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) was increased in women at 12 weeks of pregnancy, prior to diagnosis of gestational diabetes. Finally, we identified several transcription factors that may be important for controlling hormone production by the placenta and associate with pregnancy outcome. Thus, our observations suggest that analysis of the placental secretome could lead to the identification of new placental biomarkers of pregnancy complications.

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“…Since 2007, much work has been accumulated on a newly identified hereditary thrombophilic genetic factor, the ‘M2 haplotype’ of the annexin A5 ( ANXA5 ) gene. Indeed, we and others identified the M2 haplotype associated with obstetric pathologies such as gestational hypertension, preeclampsia [ 23 – 27 ], fetal growth restriction, preterm birth [ 26 , 28 – 30 ], antiphospholipid syndrome [ 31 ], and most incriminatory recurrent pregnancy losses (RPL) [ 32 ]. Moreover, in our previous studies, we confirmed risks of maternal M2/ANXA5 haplotype and identified the paternal carrier status as an equal risk factor for RPL and obstetric complications [ 23 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

Rogenhofer

Markoff²,

Ennerst

et al. 2020

J Assist Reprod Genet

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Objective This study was carried out to determine the potential role of the M2/ANXA5 haplotype as a risk factor for recurrent implantation failure (RIF). Carriage of the M2/ANXA5 haplotype that induces prothrombotic changes has been implicated in failure of early pregnancies and placenta-mediated complications (preeclampsia, IUGR, preterm birth). Material and methods In the present case control study, 63 couples (females and males) with RIF presenting for IVF/ICSI to the Fertility Center of [masked] were analyzed. RIF was defined as ≥ 4 consecutive failed ART-transfers of ≥ 4 blastocysts or ≥ 8 cleavage-stage embryos of optimal quality and maternal age ≤ 41. Fertile female controls (n = 90) were recruited from the same center. Population controls (n = 533) were drafted from the PopGen biobank, UKSH Kiel. Results Couples carrying the M2/ANXA5 haplotype turned out to have a significantly increased relative risk (RR) for RIF. Compared with female fertile controls, RR was 1.81 with p = 0.037 (OR 2.1, 95%CI 1.0–4.3) and RR was 1.70, with p = 0.004 (OR 2.0, 95%CI 1.2–3.1) compared with population controls (15.4% M2 carriers). Male partners were comparable with RIF females for M2/ANXA5 haplotypes (28.6% vs. 23.8%, p = 0.54). RIF females compared with population controls had a RR of 1.55 (p = 0.09) and RIF males compared with population controls had a RR of 1.9 (p = 0.01). Couples with ≥ 7 failed transfers showed a RR of 1.82 (p = 0.02) compared with population controls. Conclusion Our findings suggest that maternal as well as paternal M2/ANXA5 haplotype carriages are risk factors for RIF. These results allow new insights into the pathogenesis of RIF and might help to identify relevant risk groups.

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

Abstract: These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.

Cited by 7 publications

References 37 publications

Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis

Unbiased placental secretome characterization identifies candidates for pregnancy complications

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

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