Paternal and maternal carriage of the annexin A5 M2 haplotype are equal risk factors for recurrent pregnancy loss: a pilot study (original) (raw)
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Fertility and Sterility, 2013
Objective: To study the influence of M2/ANXA5 for recurrent pregnancy loss (RPL), according to the timing of miscarriages and assess the male partner risk. Design: Genetic association study. Setting: Academic research center. Patient(s): Female patients from two academic centers in Germany and Bulgaria with two or more unexplained miscarriages were selected for this study. Male partners were available for a part of the German sample. Population controls were recruited from healthy individuals of respective populations. Intervention(s): None. Main Outcome Measure(s): Incidence of M2 carriage and odds ratios were calculated between patient and control groups, and RPL risk was evaluated. Result(s): The M2 haplotype in ANXA5 was associated with greater overall RPL risk in German and in Bulgarian women, and a trend of higher prevalence was seen for male partners of German RPL patients. The highest relative risk of M2 carriage was observed in women of both populations with ''early'' fetal losses between the 10th and 15th gestational weeks, which was significant in the meta-analysis. Conclusion(s): M2 carriage seems to have an RPL risk role mostly for early abortions, gestational weeks 10-15. In the first phase of pregnancy this correlates with vascular remodeling to accomplish the transition from high-to low-resistance blood vessels. (Fertil Steril Ò
Journal of Assisted Reproduction and Genetics, 2018
Purpose Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. Methods This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. Results No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. Conclusions The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/ or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications.
Journal of assisted reproduction and genetics, 2017
The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p < 0.001). Post hoc analyses demonstrated an association for IUGR and PB individually. A strong link between previous miscarriages an...
PloS one, 2015
Annexin A5 is an essential component of placental integrity that may potentially mediate susceptibility to phenotypes of compromised pregnancy. A promoter haplotype termed M2 of the coding gene ANXA5 has been implicated in various pregnancy complications such as preeclampsia and recurrent pregnancy loss (RPL), however with inconclusive results. A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia and Denmark to estimate the RPL disease risk of the M2 haplotype in Northern Europe. Comparative prevalence of the studied ANXA5 genetic variants in human populations was estimated based on the 1000 Genomes Project (n = 675, whole-genome sequencing data) and the KORA S3 500K dataset of South German samples (n = 1644, genome-wide genotyping data). Minor allele frequency of common polymorphisms in ANXA5 promoter was up to two-fold lower among Es...
We sought to verify whether variation in the promoter of the gene encoding placental anticoagulant protein annexin A5 (ANXA5) represents a risk factor for recurrent pregnancy loss (RPL). Sequence analysis of 70 German RPL patients, all known to carry neither factor V Leiden nor a prothrombin mutation, revealed four consecutive nucleotide substitutions in the ANXA5 promoter that were transmitted as a joint haplotype (M2). Reporter gene assays revealed that M2 reduces the in vitro activity of the ANXA5 promoter to 37-42% of the normal level. The possible relationship between M2 and RPL was evaluated by comparing RPL patients to two independent control groups recruited from the registry of the Institute of Human Genetics in Münster and the PopGen biobank in Kiel, respectively. Carriers of M2 were found to exhibit a more than two-fold higher RPL risk than non-carriers (odds ratio = 2.42, 95% confidence interval: 1.27 -4.58) when using unselected controls (PopGen), and an almost four-fold higher risk when using the Münster 'super-controls', i.e. women with successful pregnancies and no previous history of pregnancy losses (odds ratio = 3.88, 95% confidence interval: 1.98 -7.54). This statistically significant association should facilitate the development of improved prognostic algorithms for RPL, involving a more precise assessment of individual disease risks, and provide a guide to offering adequate therapies where relevant. at Westfalische Wilhelms-Universitaet, Zweigbibliothek Chemie der ULB on July 28, 2015 http://hmg.oxfordjournals.org/ Downloaded from at Westfalische Wilhelms-Universitaet, Zweigbibliothek Chemie der ULB on July 28, 2015 http://hmg.oxfordjournals.org/ Downloaded from
Reproductive BioMedicine Online, 2015
Annexin A5 is a placental anti-coagulant protein that contains four nucleotide substitutions (M2 haplotype) in its promoter. This haplotype is a risk factor for recurrent spontaneous abortion (RSA). The influence of the M2 haplotype in the gestational timing of spontaneous abortions, paternal risk and relationships with known risk factors were investigated. European couples (n = 500) who had experienced three or more consecutive spontaneous abortions, and two fertile control groups, were selected for this study. The allele frequency of M2 was significantly higher among patients who had experienced early RSA than among controls (P = 0.002). No difference was found between controls and patients who had undergone late spontaneous abortions. No difference was found between patients who had experienced RSA 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. The M2 haplotype is a risk factor for early spontaneous abortions, before the 12th 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 RSA risk.
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.
Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss
Recent findings have raised the possibility that polymorphisms within the annexin A5 gene (ANXA5) promoter contribute to the etiology of recurrent pregnancy loss (RPL). In our present study, 243 Japanese women who had suffered more than three fetal losses and a group of 119 fertile controls were genotyped for four ANXA5 gene promoter single-nucleotide polymorphisms (SNPs; SNP1-4: g.-467G .A, g.-448A.C, g.-422T.C, g.-373G.A) previously reported to be associated with this disorder. An additional two SNPs located within the 5 ′ -untranslated region of the ANXA5 (SNP5 and 6: g.-302T.G, g.-1C.T) were also evaluated. Our case -control study revealed that the minor allele was significantly more frequent in the RPL group than controls for all six of these SNPs, among which SNP5 showed the highest significance (P ¼ 0.002). As with the M2 haplotype for SNP1-4 (A-C-C-A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-C-C-A-G-T), the third major haplotype in the Japanese population, showed a significantly higher frequency in our current RPL subjects than in controls (P ¼ 0.025). In addition, the second major haplotype (G-A-T-G-G-C) was found to confer a significant risk of RPL (P ¼ 0.036), implicating SNP5 as a major risk determinant for this disease. Our present findings support the hypothesis that genomic variations within the ANXA5 gene upstream region impact upon the disease susceptibility to RPL. Our data indicate that SNP5 is a novel risk factor for this disease in the Japanese population.
This study compared the incidence of M2/ANXA5 haplotype carriage, a documented repeated miscarriage risk factor, in patient groups with normal and elevated lipoprotein(a) (Lp(a)) levels. A total of 138 women with !2 consecutive, idiopathic recurrent miscarriages, categorized in patients with elevated (!30 mg/dL, n ¼ 44) and normal Lp(a) level (<30 mg/dL, n ¼ 94) were recruited at the recurrent pregnancy loss (RPL) clinic of Munich Großhadern University Hospital. A total of 500 fertile women served as controls. All patients were genotyped for ANXA5 promoter haplotypes, genetic frequencies were compared, and odds ratios (ORs) and relative risks of M2 carriers were calculated. Women with M2 haplotype had an almost 2 times higher relative risk of RPL (OR 2.6, 95% confidence interval 1.5-4.6, P ¼ .001) than fertile controls. Furthermore, risk rises to 2.47 in patients having normal Lp(a) levels (OR 3.2, 95% confidence interval 1.7-5.9, P ¼ .001), whereas women with high Lp(a) levels exhibit notably lower apparent RPL risk of 1.39 (OR 1.4, 95% confidence interval 0.5-4.1, P ¼ .659).