Annexin A5 haplotype M2 is not a risk factor for recurrent spontaneous abortion in Northern Europe: is there sufficient evidence?

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

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

Lessons From the EThIGII Trial: Proper Putative Benefit Assessment of Low-Molecular-Weight Heparin Treatment in M2/ANXA5 Haplotype Carriers

This study presents sample size considerations derived from the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIGII) trial (ClinicalTrials.gov: NCT00400387) to address the question of low-molecular-weight heparin (LMWH) treatment in women with recurrent pregnancy loss (RPL) depending on the M2/ANXA5 haplotype. To evaluate the possible influence of such treatment on miscarriage rates of trial participants, a post hoc analysis of ANXA5 promoter genotypes in the light of M2/ANXA5 (RPRGL3) distribution was performed using logistic models. DNA for genotyping was available from 129 LMWH and 95 control patients, 44 (19.6%) of whom were M2/ANXA5 carriers. Miscarriages occurred in 1 (4.0%) of 25 M2/ANXA5 carriers from the LMWH group compared to 4 (21.1%) of 19 in the control group, resulting in an odds ratio (95% confidence interval) for miscarriage of 0.16 (0.016-1.5) for women treated with LMWH. In noncarriers, miscarriage rates were 6 (5.8%) of 104 versus 7 (9.2%) of 76 for the LMWH and the control groups, respectively, corresponding to an odds ratio for miscarriage of 0.60 (0.19-1.9). The apparent beneficial effects of miscarriage rate reduction in M2/ANXA5 carriers with RPL concur with biological considerations about improvement in reduced ANXA5 function through LMWH treatment in an adequate murine model. The data obtained were instrumental to design proper assessment of the existence and magnitude of this effect

Chromosomal evolution of the PKD1 gene family in primates

Correction to Kirsch S, Pasantes J, Wolf A, Bogdanova N, Münch C, Pennekamp P, Krawczak M, Dworniczak B, Schempp W: Chromosomal evolution of the PKD1 gene family in primates. BMC Evolutionary Biology 2008, 8:263 (doi:10.1186/1471-2148-8-263

Lower Incidence of M2/ANXA5 Carriage in Recurrent Pregnancy Loss Patients With Elevated Lipoprotein(a) Levels

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 = 44) and normal Lp(a) level (<30 mg/dL, n = 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 = .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 = .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 = .659)

Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications

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.Fil: Aranda, Federico. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Udry, Sebastián. Hospital General de Agudos"Dr Carlos G. Durand"; ArgentinaFil: Perés Wingeyer, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Amshoff, Lea Christina. University Hospital Munster; AlemaniaFil: Bogdanova, Nadja. University Hospital Munster; AlemaniaFil: Wieacker, Peter. University Hospital Munster; AlemaniaFil: Latino, José Omar. Hospital General de Agudos "Carlos G. Durand"; ArgentinaFil: Markoff, Arseni. University Hospital Munster; AlemaniaFil: de Larrañaga, Gabriela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentin