Placental SNV rs8192446 in the ADORA2A gene is associated with Preeclampsia: a pilot study

Preeclampsia (PE) is one of the leading causes of maternal and fetal morbidity and mortality worldwide. An impaired trophoblast invasiveness and resulting defective remodeling of spiral arteries lead to placental hypoxia that promotes the release of different antiangiogenic and proinflammatory factors to maternal circulation. Adenosine a purine nucleoside derived from ATP metabolism, is among these factors, and high concentrations have been observed in the sera of women affected with PE. The raise in adenosine levels is linked to elevated placental expression of the adenosine A2A receptor (ADORA2A), yet the contribution of single-nucleotide variations (SNVs) in the ADORA2A gene remains unclear. The association between placental ADORA2A SNVs and preeclampsia was evaluated.

Five SNVs (rs2298383, rs4822489, rs2236624, rs17650937, and s8192446) were genotyped using real-time PCR with TaqMan probes. The functional effect of the N144K mutation was evaluated through in silico mutagenesis to assess potential structural alterations.

The SNV rs8192446 was strongly associated with PE [OR=10.42 (95% CI: 2.08-103.39, p=0.0009)], association that remained after BH correction (p=0.0009). The SNV rs8192446 was also associated with mild PE (p=0.0403) and severe PE (p=0.0072). In-silico results revealed that N144K mutation does not alter the recognition of the ligand by ADORA2A but exerts a subtle modulation of the ADORA2A-adenosine interaction.

Taken together, these results suggest that placental ADORA2A rs8192446 is functionally relevant for preeclampsia development contributing to ADORA2A hypofunction through perturbations in downstream signaling mechanisms. This is the first study to report an association between ADORA2A rs8192446 and preeclampsia susceptibility in Mexican population.