Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss (original) (raw)
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Springer eBooks, 2016
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-CC A) for a western population in previous reports, a haplotype comprising all of the minor alleles for SNP1-6 (A-CC 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-AT -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.
Objective: To study the possible contribution of paternal, in addition to maternal, carriage of M2/ANXA5 as a risk factor for recurrent pregnancy loss (RPL). Design: Case–control study. Setting: Academic research center. Patient(s): Couples presenting themselves to the Fertility Center, Ludwig-Maximilians-University Munich with two or more consecutive, unexplained miscarriages were selected for this study. Fertile female controls were from the same center and also from the resource of the Institute of Human Genetics, Westfalian Wilhelms-University Muenster. Population controls were drafted from the PopGen biobank, University Clinic Schleswig-Holstein Kiel. Intervention(s): None. Main Outcome Measure(s): Incidence of M2 carriage was estimated in patient and control groups, odds ratios were calculated, and RPL risk was evaluated. Result(s): In comparison with female fertile controls, the risk for repeated abortion in the RPL group, associated with M2 carriage, was between 1.7 and 3.8, and it was 2.3 compared with population controls. Because of the equal genetic incidence of M2, with an allelic frequency of 0.167 in the female and male partner RPL subgroups, the haplotype confers approximately the same relative risk to carriers of both sexes. Conclusion(s): Paternal M2 carriage seems to confer an equal risk for recurrent miscarriages as M2 carriage in RPL mothers. This finding points to a role of ANXA5 and the M2 haplotype in the fetus and/or the extraembryonic membranes for pregnancy pathology. Prognostic RPL algorithms might be improved by testing the male partner for M2 carriage, and
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...
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.
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.
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
Genetic analysis of the M2/ANXA5 haplotype in Syrian healthy population
International Journal of Reproduction, Contraception, Obstetrics and Gynecology, 2022
Background: Annexin A5 (ANXA5) is an abundantly and ubiquitously expressed protein showing the highest levels of concentration in kidney, liver and placenta. ANXA5 plays a central role in the machinery of membrane repair by enabling of a protective 2D bandage at membrane damaged site, has properties anti-inflammatory, pro-fibrinolytic and anti-thrombotic. Four polymorphisms have been identified in the ANXA5 promoter, which were transmitted as a joint haplotype (M2). M2 haplotype decrease the ANXA5 gene promoter activity and mRNA expression which causes several troubles. Methods: The aim of this cross-sectional study is to determine the frequency of M2/ANXA5 haplotype in healthy Syrian individuals and compare the genotype and allele distribution with other populations. In this study 94 (female, 71 and male, 23) unrelated healthy Syrian nationals were involved. 94 DNA samples have been collected in order to determine the spread the genotype M2 haplotype using allele specific polymerase chain reaction (AS-PCR). Results: Our results indicate that the distribution of the alleles and genotypes of M2 haplotype vary considerably in different populations. In the Syrian population the distribution of M2 and wide type (WT) were M2/M2 9.6%, M2/WT 44.7%, WT/WT 45.7%. The M2 haplotype was found in 45 of women (allele frequency 31%) and in 15 of men (allele frequency 32%). The distribution of the ANXA5 genotypes in Syrian study group conformed to Hardy-Weinberg equilibrium (p=0.92). Conclusions: No significant differences were found at frequency distribution of different genotypes and M2 allele between women and men within this Syrian cohort. In comparison with the results of other studies, the results of this study demonstrate that the frequency and distribution of the M2 haplotype in Syrian population are different from most other populations worldwide.
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
ANRIL rs4977574 Gene Polymorphism in Women with Recurrent Pregnancy Loss
Journal of Clinical Medicine
Background: ANRIL rs4977574 gene polymorphism has been associated with arterial thrombosis and cardiovascular disease development. ANRIL rs4977574 gene polymorphism could also be associated with recurrent pregnancy loss (RPL) since there is increasing evidence in favor of a potential shared pathophysiological mechanism with cardiovascular disease, potentially through arterial thrombosis. This study’s goal is to investigate the differences in ANRIL rs4977574 gene polymorphism between women with and without RPL, if any, as well as a potential association with the number of pregnancy losses. Methods: DNA was isolated from peripheral blood samples, and the sequence containing the polymorphism of interest was amplified with PCR. Results were visualized under UV light following electrophoresis in 3% agarose gel with ethidium bromide. ANRIL rs4977574 (A>G) prevalence was compared between 56 women with and 69 without RPL. Results were adjusted for women’s age and BMI, while a stratified ...