Recurrent pregnancy loss -associated promoter polymorphisms affect ANXA5 ge ne expression via G -quadruplex propensity

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Recent findings have highlighted the possibility that polymorphismswithin the annexin A5 gene (ANXA5) promoter contribute to the etiology of various obstetriccomplications. However, the underlying mechanisms are unknown. In our present study, thetranscriptional activity of the ANXA5gene promoter was examined in the context of G-quadruplexformation. The M2 haplotype of the promoter polymorphisms that confers a high risk of onset forthese disorders shows lower activity and less expression of ANXA5 mRNA. This gene promoterregion has a motif that potentially forms a G-quadruplex structure, and the M2 allele possesses lesspotential than the major allele. The promoter activity determined by luciferase reporter analysiscorrelated with the in vitro G-quadruplex propensity estimated by circular dichroism. Treatmentwith a G-quadruplex ligand inhibited this promoter activity. Taken together, our data indicate thatthe M2 allele instigates G-quadruplex-mediated transcriptional regulation and consequentlydownregulates the placental anticoagulation factor annexin A5 levels, leading to obstetric disorders.Our data lend support to the developing paradigm that genomic variation affects gene expressionlevels via DNA secondary structures leading to the disease susceptibility.