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In silico determination of changes in transcription factor binding sites for the preeclampsia risk haplotype in the regulatory region of the FLT1 gene
1  Institute of General Pathology and Pathophysiology, Moscow, Russia (NIIOPP)
Academic Editor: Peter Nielsen


Preeclampsia (PE) is one of the most common complications of pregnancy that occurs in 3-8% of pregnant women, being one of the top five causes of maternal morbidity and mortality. We found that PE-associated polymorphisms near the FLT1 gene are located in the same regulatory region and together can be a genetic pattern that affects the development of pathology, forming a PE risk haplotype.

We used in silico study design, using for database analysis. Under examination PubMed and GWAS-catalog we chose only SNPs located in FLT1 gene and it's regulatory area with association p-value threshold of 5 × 108. All SNPs in regulatory region were selected with MAF greater than 1 % for exclusions from the analysis of rare genetic variants. Haplotype of risk calculated with help LDhap Tool for EUR populations, including SEU,TSI, FIN, GBR, IBS based on the alleles frequency of the analyzed polymorphisms. Possible haplotype risk were determined according to PE-associated alleles of polymorphisms (rs4769612 and rs7318880), as well as comparison of the prevalence of haplotypes with the prevalence of PE in the European population. Under TFBs changes analytics in HumanTFDB we use p-value cutoff 1 × 10−4 when analyzing TFBs for all possible haplotypes. Determination of TF expression in placenta were performed with Proteomic DB database search.

We used GWAS-catalog to identify polymorphisms rs4769612 and rs7318880 in FLT1 associated with preeclampsia in the maternal and child genomes. According to UCSC genome browser (oRegAnno) 5 regulatory elements overlap: OREG1191996, OREG1658246, OREG1688336, OREG1537828 and EH38E1663332. In the regulatory region, we selected SNPs with a MAF of 1% and identified possible haplotypes in European populations using LDhap Tool. We identified 4 possible haplotypes, with frequency theoretical risk haplotype 8.25% (rs7320190-C, rs7318880-T, rs12867370-A, rs4769612-C, rs4769613-C, rs74623647-G, rs7321138-C, rs76592233-C).

Using HumanTFDB, we identified changes from 83 transcription factor binding sites (TFBs) to minus DNA strands in the analysis of all 4 possible haplotypes. Only 40 transcription factors (TFs) are expressed in the placenta, according to Proteomic DB. When analyzing the changes in TPFS, which are characteristic only for the risk haplotype with a prevalence in the European population of 0.0825, we found that 5 TPTFs change. At the same time, the number of TFBSs for ELF1, SPIB increases. The number of TFBS POLR2A, KLF15 decreases (not expressed in the placenta). The most significant is the emergence of a new TFBS KAT5, for the promoter of which only a DNase signature is observed until day 118 of pregnancy in the placenta, and after day 118 it acquires a promoter signature. Theoretically, the appearance of a new TFBS can increase the expression of FLT1, causing an imbalance of angiogenic - antiangiogenic factors, characteristic of PE.

Keywords: Preeclampsia; SNP; polymorphism; FLT1; risk haplotype; TFBs; TF