Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications

Abstract

Inherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancy-related hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls, 195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic regression, correcting for age, gravidity and parity showed that the ANXA5 haplotype is significantly and independently associated with the occurrence of RFL (3.1; 95%CI: 1.1-9.5; p = 0.047) and pregnancy-related hypertensive disorders (2.1; 95%CI: 1.2-3.5; p = 0.008). The M2 haplotype might be a new and relevant risk factor for obstetric complications.

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

“…The highest M2 carrier rates were observed in the early fetal losses subgroup, less than 15 gestational weeks, in primary and secondary RPL patients. This is in agreement with the proposed role of M2/ANXA5 as Bearly^RPL factor [4,5], in contrast to the Bclassic^thrombophilia factors FVL and PTm, of greater importance for late miscarriages, >20th week [2,34]. It should also be noted that for this study, uncertainties in the exact timing of conception should allow for ±1 to 2 weeks difference, when recording the timing of pregnancy loss similar to previous studies.…”

“…As reported in previous studies, M2 prevalence in population and healthy subject controls of German, Italian, Bulgarian, and UK white European origin are about 15-17% [4,5,14]; whereas in Asian populations, the reported carrier rate is 11% with 5.4% M2 allelic frequency for the Japanese [20]. A recent study finding no association of M2/ ANXA5 with RPL in 86 Estonian and 227 Danish subjects reported 27.3% prevalence with 15.2% allelic frequency in Estonian and 23.5% prevalence with 12.6% allelic frequency in Danish parous women [30].…”

“…The estimated odds ratios in M2 carriers were somewhat elevated, 1.8 to 3.0, when compared to healthy controls with at least one live birth and with negative history of pregnancy losses in German [5,14], Italian [4], Bulgarian [5], and Japanese [20] cohorts. However, the criteria for RPL subjects varied slightly between the studies such as the definition of RPL and categories of embryonic development.…”

“…Primary RPL comprises ≥2 consecutive RPL before the 20th GW, with no history of live birth; secondary RPL have ≥2 consecutive abortions before the 20th GW, after a live birth; and tertiary RPL represent ≥2 nonconsecutive miscarriages that occurred before the 20th GW but are interspersed with live births [27,28]. RPL was further subdivided into two subgroups based on timing of pregnancy losses: subgroup 1, Bearly^fetal losses, GW ≤15, and subgroup 2, Blate^fetal losses, GW >15 [4].…”

“…RPL is a complex and multifactorial obstetric problem with polygenic background and it involves a variety of genetic, physiological, and environment factors [2]. About 30-40% of RPL cases remain unexplained, categorized as Bidiopathic.Î n the last decade, evidence has linked hereditary thrombophilia to the etiology of RPL by a mechanism of impeded placental perfusion, ultimately resulting in adverse pregnancy outcome [3][4][5][6][7]. Although factor V Leiden (FVL) and prothrombin G20210A (PTm) variants are accounted for 70% of inherited thrombophilia patients [7], both of these factors are rare in Asian population [8,9].…”