BMI-Dependent Associations of the Estradiol-Linked Polymorphism rs117585797 of the Anoctamin-2 Gene with Pre-Eclampsia.

The aim of this study was to examine the modifying effect of body mass index (BMI) on the association of genome-wide association studies (GWAS)-significant for the level of sex hormones polymorphic loci with pre-eclampsia (PE). The work carried out genotyping of specially selected (according to data from previously conducted GWAS) 18 single nucleotide polymorphisms (SNP)that determine the content of various sex hormones in the organism. The sample of 891 pregnant women included two subgroups (they were formed based on the BMI values of women before pregnancy (pre-pregnancy BMI [preBMI]): preBMI < 25 (n = 592; 279 with PE/313 without PE) and preBMI ≥ 25 (n = 299; 152 with PE/147 without PE). The Firth's penalized regression was used for the search of associations between SNPs and PE. As a whole, in the investigated cohort of women (PE [n = 431]/control group [n = 460], n = 891), an association of interactions of rs117585797 anoctamin-2 × preBMI with PE was found: ORA = 0.86, 95%CIA = 0.76-0.96, ppermt = 0.020. The results of our associative analysis in the two cohorts under consideration indicated the presence of a significant association only among women with preBMI < 25: SNP rs117585797 anoctamin-2 (C > A) was linked with PE risk (ORA = 2.69, 95%CIA = 1.26-5.72, ppermt = 0.011, power = 91.77%). In the women group with preBMI ≥ 25, we did not identify significant associations. The PE-associated locus rs117585797 of the anoctamin-2 gene and 14 of its LD variants were functionally significant for 57 proteins involved in PE-significant biological pathways such as regulation of gene expression, hormone- and estrogen-dependent processes, embryonic development, and adipogenesis. In conclusion, this study is the first to demonstrate a BMI-specific correlation between GWAS-significant for estradiol levels polymorphism rs117585797 anoctamin-2 (C > A) and PE: this SNP was PE-associated in preBMI < 25 pregnant women and not linked with PE risk in preBMI ≥ 25 pregnant women.