Multicentre Study of the Clinical Relevance of Screening IVF Patients for Carrier Status of the Annexin A5 M2 Haplotype
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RBMO 1128 No. of Pages 8, Model 6+ 15 April 2014 Reproductive BioMedicine Online (2014) xxx, xxx– xxx www.sciencedirect.com www.rbmonline.com ARTICLE 7 4 Multicentre study of the clinical relevance 8 5 of screening IVF patients for carrier status 6 of the annexin A5 M2 haplotype a, b b c 9 Simon Fishel *, Rashmi Patel , Alison Lytollis , Jeanette Robinson , e d a a 10 Mary Smedley , Paula Smith , Craig Cameron , Simon Thornton , a b d e 11 Ken Dowell , Glenn Atkinson , Adel Shaker , Philip Lowe , c f f 12 Rahnuma Kazem , Sandra Brett , Anna Fox 13 a CARE Fertility Group, John Webster House, 6 Lawrence Drive, Nottingham Business Park, Nottingham NG8 6PZ, United 14Q1 Kingdom; b CARE Manchester, 108–112 Daisy Bank Road, Victoria Park, Manchester M14 5QH, United Kingdom; c CARE 15 Northampton, 67 The Avenue, Cliftonville, Northampton NN1 5BT, United Kingdom; d CARE Sheffield, 24–26 Glen Road, 16 Sheffield S7 1RA, United Kingdom; e CARE Nottingham, John Webster House, 6 Lawrence Drive, Nottingham Business Park, 17 Nottingham NG8 6PZ, United Kingdom; f CARE Dublin, Beacon CARE Fertility, Beacon Court, Sandyford, Dublin 18, Ireland 18 * Corresponding author. E-mail address: simon.fi[email protected] (S Fishel). Simon Fishel is CEO of CARE Fertility Group. He commenced research at Cambridge University with Bob Edwards in 1975. In 1980, he joined Patrick Steptoe and Bob at the start of Bourn Hall and was also awarded the prestigious Beit Memorial Fellowship and Research Fellowship at Churchill College. He has published more than 200 papers and three books and has received many international awards. Founder of the world’s first degree course in IVF in 1992, he was awarded to an Hominem Personal Professional Chair in 1997 and 2009 received Liverpool John Moores University highest honour of University Fellow for ‘outstanding contribution to science and to humanity’. Abstract Thrombophilia and impaired placental vasculature are a major cause of adverse pregnancy outcome. In 2007, a new hered- itary factor for obstetric complications and recurrent pregnancy loss (RPL) was identified as a sequence variation in the core promoter of the annexin A5 gene, ANXA5, called the M2 haplotype. M2 carriership has been demonstrated in couples with recurrent miscarriage and its origin is embryonic rather than specifically maternal, confirmed by subsequent papers. The M2 haplotype is the first report of a hereditary factor related to pregnancy pathology caused by embryonic-induced anticoagulation. It has been demonstrated that cou- ples with RPL had equal and significantly increased M2 carriership and that maternal and paternal carriership confers equal risk. Given its importance for patients with RPL, and potentially implantation failure, this study assessed the incidence of carrier status for the M2 ANXA5 haplotype in both the male and female of couples attending five CARE IVF centres. In 314 patients (157 couples), 44% of couples (one or both partners), 24% of females, 26% of males and 37% of couples with unexplained infertility were M2 carriers. This high incidence has provoked further urgent studies on specific patient populations and on the value of post embryo-transfer therapy. RBMOnline ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. 11 KEYWORDS: ANXA5, infertility, miscarriage, recurrent pregnancy loss, thrombophilia http://dx.doi.org/10.1016/j.rbmo.2014.03.019 1472-6483/ª 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Fishel, S et al. Multicentre study of the clinical relevance of screening IVF patients for carrier status of the annexin A5 M2 haplotype. Reproductive BioMedicine Online (2014), http://dx.doi.org/10.1016/j.rbmo.2014.03.019 RBMO 1128 No. of Pages 8, Model 6+ 15 April 2014 2 S Fishel et al. 12 Introduction from women with fetal growth restriction and or 71 pre-eclampsia) is the result of carriage of the M2 haplotype, 72 13 Thrombophilias are a major cause of adverse pregnancy out- but that this occurred regardless of parental origin, with 73 14 come (Markoff et al., 2011) and there is increasing evidence obvious consequences for embryonic- rather than wholly 74 15 to suggest that impairment of placental vasculature maternal-induced risk. They observed that the normal 75 16 increases the risk of recurrent pregnancy loss (RPL), intra- ANXA5 allele does not compensate for observed M2 76 17 uterine fetal death, gestational hypertension, pre-eclamp- allele-specific decreased mRNA concentrations and made 77 18 sia, venous thromboembolism, fetal growth restriction and the significant finding that, unlike Factor V Leiden and pro- 78 19 small-for-gestational-age (SGA) newborns (Chinni et al., thrombin where paternal thrombophilic genes are not asso- 79 20 2009; Grandone and Margaglione, 2003; Grandone et al., ciated with RPL (Toth et al., 2008), the M2 ANXA5 allele acts 80 21 2010; Tiscia et al., 2009, 2012; Younis and Samueloff, via the embryo. 81 22 2003). The work of Markoff et al. (2010) led to a pilot study of 30 82 23 Normal pregnancy is an acquired hypercoagulable state RPL couples where all other causes of RPL had been excluded 83 24 and therefore women with a genetic predisposition to (including inherited thrombophilias and APS; Rogenhofer 84 25 thrombophilia may develop clinical signs of coagulation et al., 2012). The study confirmed that male and females 85 26 defects de novo during pregnancy or during the post-partum in these RPL couples had equal and significantly increased 86 27 period (Chunilal and Bates, 2009; Rey et al., 2003). The pre- M2 carriership when compared with control populations. 87 28 disposing role of hereditary thrombophilic factors has been The authors concluded that paternal and maternal carriage 88 29 reported in several clinical studies (Rodger et al., 2010), of the M2 ANXA5 haplotype associate with RPL and confer 89 30 and historically, in the majority of patients, the hereditary equal risks. They further reported that M2 ANXA5 is the first 90 31 factor has been Factor V Leiden or prothrombin (Bick, instance of a hereditary factor causing pregnancy pathology 91 32 2000). However, in 2007 a new hereditary factor for RPL by affecting embryonic anticoagulation (Rogenhofer et al., 92 33 and additional thrombophilia-related obstetric complica- 2012). 93 34 tions was identified (Bogdanova et al., 2007; Chinni et al., Tu¨ttelmann et al. (2012) undertook a risk stratification 94 35Q2 2010). This defect, termed the M2 haplotype, is a sequence study of an IVF cohort of 695 German women compared with 95 36 variation in the core promoter of the annexin A5 gene, 500 fertile female controls and 533 population controls. The 96 37 ANXA5. It consists of four consecutive nucleotide substitu- carriers of the M2 haplotype had a higher relative risk (1.4) 97 38Q3 tions in the core promoter and results in reduced expression of belonging to the IVF group in comparison with fertile 98 39 of ANXA5 in placentas from M2 haplotype carriers when female controls and a higher relative risk (1.2) compared 99 40 compared with noncarriers. with population controls. This overall risk was due to a sub- 100 41 Annexin A5 is a member of the annexin protein family group of women with previous pregnancy losses and for this 101 42 which share the properties of binding calcium and phospho- group the relative risks were 3.8 and 2.3, respectively. The 102 43 lipids. It is distributed abundantly and ubiquitously, mostly authors reported that there was no association with bio- 103 44 in the kidney, liver and placenta (Morgan et al., 1998). It chemical pregnancy loss, implantation rate, ovarian 104 45 is most abundant on the apical membranes of placental reserve, hormone status, number and quality of egg cells 105 46 syncytiotrophoblasts, the interface between maternal and and general embryonic development. However, there was 106 47 fetal circulation. ANXA5 was originally named ‘placental no male partner genotyping data available. 107 48 anticoagulant protein’. It has been extensively studied both Ueki et al. (2012) in their knockout murine model found 108 49 in vivo and in vitro (Romisch et al., 1991; Thiagarajan and significant reductions both in litter size and fetal weight in 109 50 Tait, 1990). It has potent anticoagulant properties associ- ANXA5-null mice (ANXA5-KO) and thus demonstrated that 110 51 ated with its phospholipid-binding activity and is one of the maternal supply of ANXA5 to the circulation was crucial 111 52 the few annexins to be found extracellularly (Gerke et al., for maintaining normal pregnancy. They further observed 112 53 2005). The ability of ANXA5 to form two-dimensional aggre- that cross-breeding of ANXA5-KO and wild-type mice 113 54 gates on cell membranes has led to the development of the showed that only litters bred using ANXA5-KO females had 114 55 ANXA5 ‘protective shield’ model that postulates that ANXA5 reduced numbers of pups. They also demonstrated that 115 56 shields phospholipids at this site from availability for coag- administration of heparin on pregnancy days 12, 14 and 16 116 57 ulation reactions and thus contributes to the maintenance to ANXA5-KO mice significantly increased litter size. 117 58 of blood fluidity in the placenta. Annexin 5 is deficient in Evidence to date suggests that maternal and paternal 118 59 placentas of patients with antiphospholipid syndrome (APS), carriage of the M2 ANXA5 haplotype confers equal risks 119 60 and antiphospholipid antibody-mediated reduction of and acts via the embryo, causing pregnancy pathology by 120 61 annexin 5 on vascular endothelium may also contribute to affecting embryonic coagulation unlike the other well- 121 62 systemic thrombosis (Rand, 1999). Bogdanova et al. (2012) characterized thrombophilias. Additionally there is a high 122 63 revisited the annexin A5 protective shield model and incidence of carrier status in both control and subfertile 123 64 reported that preliminary genotyping analysis of a cohort populations, including patients with RPL.