Polymorphisms in the annexin A5 gene promoter in Japanese women with recurrent pregnancy loss

Abstract

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= 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= 0.025). In addition, the second major haplotype (G-A-T-G-G-C) was found to confer a significant risk of RPL (P= 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.

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

“…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.…”

Two common SNPs in pri-miR-125a alter the mature miRNA expression and associate with recurrent pregnancy loss in a Han-Chinese population

“…16 SNP located within the 5'-untranslated region of the ANXA5 (SNP g-302T>G) was a major risk determinant for RPL in the Japanese population. 17 Besides, a significant association was found between ACE DD and AT1R CC genotype and fetal loss. The effect of the ACE DD genotype on the risk of fetal loss was higher in AT1R C allele carriers.…”

Investigation of the Annexin A5 M2 haplotype in 500 white European couples who have experienced recurrent spontaneous abortion

“…German women with RM (Bogdanova et al 2007), and reproduced in cohorts of 103 Italian (Tiscia et al 2009) and 243 Japanese women (Miyamura et al 2011). Recently these findings have been confirmed in populations of 243 German and 236 Bulgarian patients with RM (Tüttelmann et al 2013).…”

“…In fact, subsequent studies have shown that the M2 haplotype is present in 11% of fertile Japanese controls and 21% in RM Japanese patients (Miyamura et al 2011), and in 15% of European populations and 21-30% in RM patients of European origin (Tüttelmann et al 2013;Tiscia et al 2009). No significant association of the M1 haplotype was found with RM.…”