Investigation of the Annexin A5 M2 haplotype in 500 white European couples who have experienced recurrent spontaneous abortion

Abstract

Annexin A5 is a placental anti-coagulant protein that contains four nucleotide substitutions (M2 haplotype) in its promoter. Studies have shown that this haplotype is a risk factor for recurrent miscarriage (RM). Our aim was to investigate the influence of the M2 haplotype in the gestational timing of miscarriages, assessing the paternal risk and investigate for relationships with known risk factors. Five hundred white European couples with three or more consecutive miscarriages and two fertile control groups were selected for this study.The allele frequency of M2 was found to be significantly higher among early RM patients than among controls (P=0.002) and there was no difference between controls and patients with late miscarriages. Moreover, there was no difference between RM patients who had a live birth or no live births or between patients who were positive or negative for known risk factors. Male and female partners in each group had similar allele frequencies of M2. In conclusion, the M2 haplotype is a risk factor for early miscarriages, before the 12 th week of gestation and confers about the same relative risk to carriers of both sexes. Having one or more M2 allele(s) in combination with other risk factors further increases the RM risk.

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

“…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.…”

“…The observed HWE deviation in M2 distribution for parous controls is analogous to other selected fertile control groups from previous studies [14,22]. A possible explanation is the positive ascertainment bias resulting from selection of the Malay parous control group comprised only of women with at least one successful pregnancy and without miscarriages or other gestational pathology, whereas spontaneous abortion generally occurs in about 10% of women worldwide [33].…”

“…Without exception, the analysis showed that 2 and 3 M2/ANXA5 alleles are significantly associated with Bearly^RPL (p = 0.01). Likewise, if both partners are M2/ANXA5 carriers, they would have higher chances to experience RPL (p = 0.03), specifically enriched in the subgroup of Bearly^fetal losses between the 6th and 15th gestational weeks, similar to the UK cohort study [22].…”

“…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].…”

Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome

“…The annexin A5 M2 haplotype (ANXA5 M2) is associated with reduced expression of ANXA5 in placentas from M2 haplotype carriers presenting with PE and FGR (Ota et al, 2013, Chinni et al, 2009, Markoff et al, 2010). Further, the M2 haplotype is associated with an increased risk of PMPCs: recurrent pregnancy loss (RPL) (Bogdanova et al, 2007, Tiscia et al, 2009, Miyamura et al, 2011, Rogenhofer et al, 2012, Tüttelmann et al, 2013, Hock et al, 2015, Demetriou et al, 2015), FGR (Tiscia et al, 2009) small for gestational age infants (Tiscia et al, 2012), and gestational hypertension (Tiscia et al, 2009). The haplotype is transmitted equally by males and females (Ota et al, 2013, Chinni et al, 2009, Markoff et al, 2010, Rogenhofer et al, 2012).…”